N⁶-甲基腺苷(m⁶A)RNA甲基化在心血管系统的表观遗传学作用

Epigenetic role of N 6 -methyladenosine (m 6 A) RNA methylation in the cardiovascular system N 6 -甲基腺苷(m 6 A)RNA甲基化在心血管系统的表观遗传学作用 first-author corresp ‡Corresponding Author ‡Corresponding Author †E-mail:xiangqing_kong@sina.com †E-mail:xiangqing_kong@sina.com xiangqing_kong@sina.com Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China As the most prevalent and abundant transcriptional modification in the eukaryotic genome, the continuous and dynamic regulation of N 6 -methyladenosine (m 6 A) has been shown to play a vital role in physiological and pathological processes of cardiovascular diseases (CVDs), such as ischemic heart failure (HF), myocardial hypertrophy, myocardial infarction (MI), and cardiomyogenesis. Regulation is achieved by modulating the expression of m 6 A enzymes and their downstream cardiac genes. In addition, this process has a major impact on different aspects of internal biological metabolism and several other external environmental effects associated with the development of CVDs. However, the exact molecular mechanism of m 6 A epigenetic regulation has not been fully elucidated. In this review, we outline recent advances and discuss potential therapeutic strategies for managing m 6 A in relation to several common CVD-related metabolic disorders and external environmental factors. Note that an appropriate understanding of the biological function of m 6 A in the cardiovascular system will pave the way towards exploring the mechanisms responsible for the development of other CVDs and their associated symptoms. Finally, it can provide new insights for the development of novel therapeutic agents for use in clinical practice. 作为真核生物基因组中最普遍和最丰富的转录修饰, N 6 -甲基腺苷(m 6 A)持续而动态性的调节在缺血性心力衰竭、心肌肥大和心肌梗死等心血管系统疾病的生理和病理过程中发挥着重要作用.此外,m 6 A RNA甲基化通过改变多种m 6 A酶及下游靶基因的表达,对与心血管系统疾病发生发展相关的内在生物代谢和外在环境因素起着重要的调节作用.但是,目前仍不清楚m 6 A表观遗传调节具体的分子生物学机制.在此,我们概述了m 6 A RNA甲基化最新的研究进展及其在常见心血管系统疾病和心血管相关代谢紊乱病理发展中的作用.这将有助于我们正确了解m 6 A在心血管系统中的生物学作用,并为进一步探索心血管疾病及其相关临床症状的发生机制和开发临床治疗药物,提供新的理论依据和思路. N 6 -methyladenosine (m 6 A) RNA methylation Cardiovascular system Metabolic disorder N 6 -甲基腺苷(m 6 A) RNA甲基化 心血管系统 代谢紊乱 Introduction 1 Epigenetics has attracted considerable attention in the biomedical field. Accumulating evidence has shown that epigenetic alterations can affect a variety of common pathological reactions, including ischemia, inflammation, aging, and tumorigenesis (He et al., 2013 2013 ). Epigenetics can also have a vital impact on gene expression and function without altering the base sequence of DNA. Moreover, these effects are reversible, heritable and are influenced by the external environment (Gibney and Nolan, 2010 2010 ; Mazzio and Soliman, 2012 2012 ). Current epigenetic mechanisms include mainly DNA methylation, post-translational histone modification, chromatin remodeling, and deployment of non-coding RNA. Recent advances in the field of epigenetics can aid our understanding of a series of complicated biological processes associated with aging (Rodriguez-Rodero et al., 2010 2010 ), development (Smith et al., 2012 2012 ), inflammation (Bayarsaihan, 2011 2011 ), immunity (Fernández-Morera et al., 2010 2010 ), stem cell biology (Calvanese and Fraga, 2012 2012 ), and angiogenesis (Buysschaert et al., 2008 2008 ). The role of reversible RNA methylation has just begun to attract worldwide scientific attention compared with the processes of DNA methylation and histone modification which are now well-established in genetics and cell biology (He, 2010 2010 ; Panneerdoss et al., 2018 2018 ). As an important part of developing RNA epigenetics, the modification of N 6 -methyladenosine (m 6 A) has recently been explored in the cardiovascular field (Liu and Pan, 2015 2015 ). It has been shown that the m 6 A modification is the most universal and abundant internal modification of eukaryotic messenger RNA (mRNA) and long non-coding RNA (lncRNA) and occurs mainly in the 3'-untranslated regions (3'-UTRs) and nearby the stop codons of the mRNA molecules (Parashar et al., 2018 2018 ; Gan et al., 2019 2019 ). Furthermore, several independent lines of evidence have revealed that the continuous and dynamic regulation of m 6 A may have a far-reaching impact on modulating the expression of specific genes (Niu et al., 2013 2013 ). In this review, we outline recent advances and discuss potential therapeutic strategies for managing m 6 A in relation to several common cardiovascular diseases (CVDs), related metabolic disorders, and external environmental factors. Biological function of m 6 A modification 1 Methyltransferase and demethylases of m 6 A 2 It has been shown that m 6 A methylation is catalyzed by the multicomponent RNA methyltransferase complex, RNA demethylases, and m 6 A readers (Liu et al., 2014 2014 ). The core components of the RNA methyltransferase complex include methyltransferase-like 3/14 (METTL3/14) and Wilms tumor 1 associated protein (WTAP) (Liu et al., 2014 2014 ). Among them, the spliceosome-associated protein WTAP has recently been found to play its role by recruiting RNA METTL3/14 to sites of methylation in the nucleus (Liu et al., 2014 2014 ). Although the methyltransferase complex of m 6 A methylation has not been fully elucidated, remarkable progress including the discovery of ALKB homolog 5 (ALKBH5) and fat mass-and obesity-related proteins (FTOs) has recently been made. The so-called erasers of specific markers operate on target transcripts via an α-ketoglutarate-and Fe 2+ -dependent way in the m 6 A and N 6 ,2'- O -dimethyladenosine (m 6 A m ) of mammalian poly-adenylated RNA (Gerken et al., 2007 2007 ; Niu et al., 2013 2013 ; Mauer et al., 2017 2017 ). In addition to the methyltransferase complex and demethylase enzyme, m 6 A is also regulated by the activity of m 6 A readers, such as YT521-B homology (YTH) m 6 A RNA-binding proteins (YTHDF), which can regulate the stability and degradation of RNAs and affect the efficiency of target mRNA translation (Wang and He, 2014 2014 ; Kennedy et al., 2016 2016 ). Therefore, m 6 A regulates its effects mainly by recruiting a variety of proteins containing the YTH domains and via its assembly by methyltransferases that are located in relative consensus motifs following transcription (Wei and Moss, 1977 1977 ; Patil et al., 2018 2018 ). The m 6 A modification may not only affect the secondary structure of mRNA and the interactions between mRNA-protein and mRNA-small nuclear RNA (snRNA), but may also be involved in modulating translatability, RNA transport and splicing, and susceptibility to post-transcriptional silencing (Zhong et al., 2008 2008 ). m 6 A regulation in the eukaryotic genome 2 It is believed that m 6 A methylation plays an important role in the regulation of gene expression by affecting the stability, degradation, and translation of RNA (Fu et al., 2014 2014 ; Meyer et al., 2015 2015 ). Several studies have confirmed that alteration of m 6 A levels may have a significant impact on various biological processes in mammals, such as the maintenance and differentiation of embryonic stem cells (ESCs), transcriptional splicing, nuclear RNA export, protein translation control, cell fate determination, circadian rhythm modification, heat shock response, meiotic progression, and neuronal function (Guo et al., 2017 2017 ; Roignant and Soller, 2017 2017 ; Wei et al., 2017 2017 ). Moreover, a lack of m 6 A modification can lead to the development of several diseases, such as obesity, cancer, type 2 diabetes mellitus (T2DM), infertility, and developmental arrest (Wei et al., 2017 2017 ). Therefore, attention has been focused on the role and importance of m 6 A regulation in the eukaryotic genome in relation to physiological and pathological processes. The m 6 A profiles of full transcriptomes have shown that m 6 A modifications occur in countless RNA transcripts with unique patterns of distribution. Although the role of m 6 A editors in the processing, synthesis, and degradation of mRNAs and proteins has been discovered (Patil et al., 2018 2018 ), the functions and mechanisms of most RNA modifications found in mRNA molecules remain poorly understood, especially with regard to the development of CVDs. m 6 A RNA modification in CVDs 1 Due to improvements in the standard of living and medical care, CVD mortality has declined markedly in certain high-income countries of Western Europe and North America (Libby et al., 2013 2013 ). However, CVD remains the leading cause of death worldwide in both developed and developing countries (Iyen et al., 2019 2019 ). Accumulating evidence has shown the contribution of several important but underappreciated issues, such as air pollution, to the genesis and development of CVDs (Cosselman et al., 2015 2015 ; Peña and Rollins, 2017 2017 ). Epigenetics plays an effective and leading regulatory role in modulating cardiovascular repair functions (Jin et al., 2019 2019 ). Therefore, new concepts and therapeutic measures must be developed for myocardial repair and regeneration to improve cardiac function. However, although certain transcription factors and co-activators have been studied in heart failure (HF), post-transcriptional modifications that mediate specific mRNAs affecting the main protein expression and cardiac function have not been explored in detail. As a key enzyme of m 6 A, FTO is widely expressed in cardiac ventricular tissues, with a high level of expression in humans (Boissel et al., 2009 2009 ). Therefore, particular attention must be paid to the possible associations between m 6 A and the physiological and pathological processes of different CVDs. Emerging evidence has identified epigenetic regulation of m 6 A and suggested possible therapeutic strategies for treating the development of cardiac defects, including ventricular septal and atrio-ventricular defects (Boissel et al., 2009 2009 ), arrhythmias (Carnevali et al., 2014 2014 ), coronary heart disease (Gustavsson et al., 2014 2014 ), and cardiomyocyte hypertrophy (Dorn et al., 2019 2019 ) (Fig. 1 1 ). m 6 A methylation is catalyzed by the multicomponent RNA methyltransferase complex (methyltransferase-like 3/14 (METTL3/14), Wilms tumor 1 associated protein (WTAP), and KIAA1429), RNA demethylases (ALKB homolog 5 (ALKBH5) and fat mass-and obesity-related protein (FTO)), and m 6 A readers (YT521-B homology (YTH) domain family 1/2/3 (YTHDF1/2/3), YTH domain containing 1 (YTHDC1), heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1), and E74-like factor 3 (elF3)). Modification of m 6 A may not only affect the secondary structure of messenger RNA (mRNA) and the interactions between mRNA-protein and mRNA-small nuclear RNA (snRNA), but may also be involved in modulating translatability, RNA transport and splicing, and susceptibility to post-transcriptional silencing. Furthermore, emerging evidence has identified the epigenetic regulation of m 6 A and suggested possible therapeutic strategies for treating the development of cardiac defects and internal metabolic disorders, including heart failure, myocardial infarction, cardiomyocyte hypertrophy, obesity, and diabetics mellitus. TFEB: transcription factor EB; MAP3K6: mitogen-activated protein kinase (MAPK) kinase kinase 6; MAP4K5: MAPK kinase kinase kinase 5; Nppa: natriuretic peptide precursor (Npp)-A; MyD88S: splice variant of myeloid differentiation factor 88; SERCA2a: sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2a; MYH7: β-myosin heavy chain 7; Ryr2: ryanodine receptor 2; Angptl4: angiopoietin-like 4; Per2: period 2; Arntl: aryl hydrocarbon receptor nuclear translocator like; FOXO1: forkhead box O1; G6PC: glucose-6-phosphatase (G6Pase) catalytic subunit; DGAT2: diacylglycerol acyltransferase 2; RBW15: RNA-binding motif protein 15; HuR: human antigen R; hnRN: heterogeneous nuclear ribonucleoprotein; CCR4-NOT: carbon catabolite repressor protein 4-negative on TATA Ischemic heart diseases 2 By altering the oxygenation capacity of cardiomyocytes directly, ischemic heart disease caused by stenosis or occlusion of the myocardial coronary artery is considered one of the main causes of morbidity and mortality worldwide, including myocardial infarction (MI) and HF (Ge et al., 2019 2019 ). Several studies have shown that cardiomyocytes under chronic anoxic conditions, such as anemia, chronic intermittent hypoxia, and sleep apnea, can retain the homeostasis of heart contractile function and energy metabolism by triggering the corresponding regulation pathways and mediating cardiac metabolic remodeling via induction of transcription (Essop, 2007 2007 ; Cole et al., 2016 2016 ). As one of the main drivers of metabolic disturbance in ischemic disease and MI, hypoxia is the result of multiple physiological and pathological stimuli (da Luz Sousa Fialho et al., 2019 2019 ). Previous studies of cardiac ventricular biopsies from patients who had undergone coronary artery bypass surgery have shown that hypoxia inducible factor (HIF) is a major transcription factor with significantly increased activity in the early period of post-MI (Lee et al., 2000 2000 ; Smith et al., 2008 2008 ). It is well-established that HIF-1 activates most of the regulatory factors involved in oxygen homeostasis in mammals by binding to hypoxia response elements (HREs) and activating the transcription of multiple target genes which may play a critical role in the hypoxic response at both the cellular and the systemic levels. Subsequently, this process regulates the relevant signal transduction pathways and the corresponding microenvironments of the pathological blood vessels induced by hypoxia and ischemia (Ortiz-Barahona et al., 2010 2010 ). Due to the deficiency in oxygen availability, cellular metabolism of cardiomyocytes is one of the major changes that occur during chronic adaptation to hypoxia (Dang and Semenza, 1999 1999 ). In addition to metabolism, the binding between HIF and HREs can be affected by epigenetic mechanisms, such as CpG methylation and oxidative DNA damage caused by hypoxia and reactive oxygen species (ROS) (Rodriguez et al., 1997 1997 ). It has also been reported that HIF-1 is associated with hypoxia and may be regulated by histone methylation directly. With regard to certain common methylases, several studies have shown that hypoxia induces the expression of ALKBH5 in various types of breast cancer cells (Essop, 2007 2007 ). In addition, el Azzouzi et al. ( 2013 2013 ) confirmed the binding sites of FTO mRNA for several hypoxia-induced cardiac microRNAs (miRs) well-known to be up-regulated in HF, such as miR-21, miR-24, miR-488, miR-224, and miR-489. These results suggest that epigenetic regulation of hypoxia may play a significant role in the pathogenesis of CVDs. In hypoxia/reoxygenation (H/R)-treated cardiomyocytes and ischemia/reperfusion (I/R)-treated mouse heart tissues, the modification of m 6 A was increased by METTL3, which is the main factor of abnormal m 6 A regulation. This was caused by promoting the translation of specific mRNAs (Lin et al., 2016 2016 ; Song et al., 2019 2019 ). The silencing of METTL3 can increase autophagic flux and inhibit apoptosis in H/R-treated cardiomyocytes, suggesting that METTL3 is a negative regulator of autophagy, which determines the cellular and systemic function of H/R-treated cardiomyocytes (Song et al., 2019 2019 ). METTL3 methylates transcription factor EB ( TFEB ), a key gene involved in lysosomal biogenesis during the autophagic process, at two m 6 A residues in the 3'-UTR. METTL3 enhances the binding of the protein heterogeneous nuclear ribonucleoprotein D (hnRNPD) to TFEB pre-mRNA, thereby decreasing the expression level of TFEB (Pastore et al., 2016 2016 ). Further experiments have shown that the autophagic flux enhanced by METTL3 deficiency is TFEB-dependent. Therefore, it is reasoned that METTL3 knockdown can increase the levels of the green fluorescent protein (GFP)-TFEB protein by up-regulating the endogenous levels of TFEB via the adenosine monophosphate (AMP)-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway (Song et al., 2019 2019 ). 3.1.1 Heart failure Current evidence shows that dysregulation of m 6 A levels in RNA can lead to the development of several pathological mechanisms, such as HF, at the molecular, cellular, and organic levels (Jia et al., 2011 2011 ; Meyer et al., 2012 2012 ). Mathiyalagan et al. ( 2019 2019 ) confirmed that the increased expression of m 6 A induced by ischemia and hypoxia may be reduced by altering the expression of FTOs. This evidence was reported in a study of different models of HF and hypoxic primary cardiomyocytes (Mathiyalagan et al., 2019 2019 ). In addition to improving cardiomyocyte function and attenuating cardiac remodeling in HF by restoring the expression of relative proteins, such as sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2a (SERCA2a), experimental evidence has shown that FTO overexpression decreases cardiac fibrosis and promotes angiogenesis in models of MI (Mathiyalagan et al., 2019 2019 ). Furthermore, it has been shown that cardiac contractile transcripts associated with ischemia and hypoxia are demethylated selectively by FTO, which can increase the stability of mRNA and protein expression (Hess et al., 2013 2013 ). 3.1.2 Myocardial infarction MI is a heart attack caused by the formation of plaque in the interior walls of the arteries that reduces blood flow to the heart and damages the heart muscles due to tissue inflammation and scarring (Lu et al., 2015 2015 ). Epicardial specificity in response to injury occurs by down-regulating a group of genes expressed differentially in the epicardium (Bochmann et al., 2010 2010 ). This is considered one of the main mechanisms of MI development. During embryogenesis, the proepicardium differentiates into cardiac vasculature and interstitial cells and eventually becomes a single epithelial cell layer covering the heart, which is essential for normal development (Reese et al., 2002 2002 ; Cai et al., 2008 2008 ; Zhou et al., 2008 2008 ; van Wijk et al., 2009 2009 ). However, it remains controversial whether the epicardium can differentiate into endothelial cells of the vasculature (Smart et al., 2007 2007 ; Winter and Groot, 2007 2007 ) and whether it can contribute directly to the formation of the myocardium (Zhou et al., 2008 2008 ). Although previous study has shown that the epicardium can regulate cardiac regeneration following injury (noted in lower vertebrates), it has also been reported that epicardial cell genes may be a promising therapeutic target following the injury of left coronary artery (LCA) ligation by the application of transcriptomics (Bochmann et al., 2010 2010 ). Therefore, these studies suggest that the involvement of epigenetics should be explored with regard to MI. Mathiyalagan et al. ( 2019 2019 ) demonstrated that the levels of FTO in mice were down-regulated within 4 h following MI induction by LCA. Furthermore, they examined cardiac remodeling soon after MI and demonstrated that maintenance of FTO expression for nearly one week could be helpful in protecting and repairing the function of cardiomyocytes by improving cardiac homeostasis. Overexpression of FTO was caused by adenoviral transfection. These data suggested the use of FTO or FTO mimics for therapeutic targeting. Hypertrophy 2 Hypertrophic cardiomyopathy is one of the common causes of myocardial injury accompanied by pathological phenomena, such as myocardial hypertrophy (Hou et al., 2017 2017 ; Liu et al., 2019 2019 ). In addition to other common stimuli, Dorn et al. ( 2019 2019 ) confirmed that methylation regulated by METTL3 on N 6 -adenosines is essential for the pathological process of hypertrophy in vivo and in vitro. Although the increase in the expression level of METTL3, which acts with METTL14, WTAP, or other regulatory subunits, may cause cardiomyocyte remodeling, it is notable that the inhibition of its activity can abrogate the ability of cardiomyocytes to cause cardiac compensatory hypertrophy in response to hypertrophic stimuli, such as aging and stress. Furthermore, cardiac-specific METTL3 knockout mice were shown to promote eccentric cardiomyocyte remodeling and dysfunction in vivo (Liu et al., 2014 2014 ; Dorn et al., 2019 2019 ). These data highlight that the dynamic methylation and modification mediated by METTL3 are necessary for regulating the myocyte growth response. Since both METTL3 and FTO are localized in the nucleus of isolated cardiac myocytes, FTO knockdown was found to decrease the augmented size of neonatal rat cardiac myocytes (NRCMs) induced by α-adrenergic stimulation in vitro (Kmietczyk et al., 2019 2019 ). Taken collectively, these results suggest that m 6 A methylation may be a novel and vital epigenetic mechanism that should be studied in relation to the maintenance of cardiac homeostasis. In addition, due to the tissue specificity of different ALKBH proteins, it is still debatable whether they can be used with similar therapeutic effects as those of the METTL3-containing protein, which is expressed ubiquitously (Fedeles et al., 2015 2015 ). Abnormal cardiac development 2 The consensus sequence contained in m 6 A is highly homologous between human and mouse species, and their mRNA levels are regulated in a tissue-specific manner from the embryonic period to adulthood (Dominissini et al., 2012 2012 ; Meyer et al., 2012 2012 ). Higher m 6 A expression in embryogenesis than in adult tissues has suggested the critical importance of m 6 A during growth and development at the cellular and organic levels. Mouse ESCs (mESCs) are well-known for their roles in embryonic development. Wang et al. ( 2014 2014 ) reported that METTL3 and METTL14 can modify m 6 A to maintain and even improve the self-renewal capability of mESCs. Their enrichment analysis indicated that m 6 A editing might be associated with the stability of RNA, which was in turn negatively associated with regulatory proteins by blocking the binding of human antigen R (HuR)’s RNA, thereby retaining the biological function of mESCs (Wang et al., 2014 2014 ). Moreover, in a study of growth retardation and developmental delay, FTO and its homozygous mutant were shown to play a vital role in the early development of the human central nervous and cardiovascular systems by maintaining the stability of 2-oxoglutarate turnover and N -methyl-nucleoside demethylase activity (Daoud et al., 2016 2016 ). Downstream gene expression 2 Alteration in the expression levels of myocardial genes in response to different pathological stimuli plays a major role in the occurrence and progression of HF in several animal models (Tan et al., 2002 2002 ). A recent study has highlighted the importance of specific modifications that occur in reversible mRNA sequences that control gene expression at the epigenetic level (Tan et al., 2002 2002 ). As an increase in the levels of m 6 A methylation is associated with cardiomyopathy, it is meaningful to investigate the role of internal m 6 A modification on the expression of the associated genes. Dynamic m 6 A methylation can influence the stability of transcription by regulating the efficiency of mRNA translation in stressed cardiomyocytes. For example, in addition to the size and cardiac function of cardiomyocytes, the expression of the downstream markers natriuretic peptide precursor (Npp)-A (Nppa) and -B (Nppb) that are associated with hypertrophy can be influenced by the enzymatic activity of METTL3. This suggests that m 6 A modification plays an integrative role in the regulation of cardiac gene expression and cellular growth response in vivo and in vitro (Kmietczyk et al., 2019 2019 ). Overall, the engineering and manipulation of m 6 A enzymes or any other type of small molecule at specific sites may be a novel therapeutic avenue for several cardiac diseases caused by dysregulation of m 6 A, such as HF and MI (James et al., 2003 2003 ). m 6 A RNA modification is an internal metabolic disorder caused by external environmental factors 1 Different studies have attempted to understand the important and necessary role of m 6 A in relation to metabolism and environmental effects that can, in turn, lead to the development of pathophysiology and abnormal heart function noted in CVDs (Table 1 1 ). m 6 A: N 6 -methyladenosine; METTL3: methyltransferase-like 3; ALKBH5: ALKB homolog 5; FTO: fat mass-and obesity-related protein; YTHDF2: YT521-B homology (YTH) domain family 2; TFEB : transcription factor EB; SERCA2a : sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2a; Nppa : natriuretic peptide precursor (Npp)-A; MYH7 : β-myosin heavy chain 7; Ryr2 : ryanodine receptor 2; MAP3K6 : mitogen-activated protein kinase (MAPK) kinase kinase 6; MAP4K5 : MAPK kinase kinase kinase 5; HuR : human antigen R; Angptl4 : angiopoietin-like 4; PPARγ : peroxisome proliferator-activated receptor γ; C/EBPα : CCAAT enhancer-binding protein α; FOXO1 : forkhead box O1; G6PC : glucose-6-phosphatase (G6Pase) catalytic subunit; DGAT2 : diacylglycerol acyltransferase 2; Per2 : period 2; Arntl : aryl hydrocarbon receptor nuclear translocator like; MyD88S : splice variant of myeloid differentiation factor 88; H/R: hypoxia/reoxygenation; NRCM: neonatal rat cardiac myocyte; mESCs: mouse embryonic stem cells; FAM134B: family with sequence similarity 134 member B; LPS: lipopolysaccharide; hDPCs: human dental pulp cells Disease Molecule Target gene Function Regulation Mechanism Reference 2 Ischemic heart diseases METTL3 TFEB Writer Up-regulation Silencing METTL3 enhances autophagic flux and inhibits apoptosis in H/R-treated cardiomyocytes by TFEB Pastore et al., 2016 2016 ALKBH5 TFEB Eraser Down-regulation ALKBH5 overexpression enhances autophagic flux and inhibits apoptosis in H/R-treated cardiomyocytes by TFEB Pastore et al., 2016 2016 Heart failure (HF) FTO SERCA2a Eraser Down-regulation FTO overexpression improves cardiomyocyte function and attenuatis cardiac remodeling in HF by regulating SERCA2a Mathiyalagan et al., 2019 2019 Myocardial infarction (MI) FTO Nppa / MYH7 / Ryr2 / SERCA2a Eraser Down-regulation FTO overexpression protects and repairs cardiomyocyte function through improving cardiac homeostasis after MI Mathiyalagan et al., 2019 2019 2 Hypertrophy METTL3 MAP3K6 / MAP4K5 / MAPK14 / Nppa / Nppb Writer Up-regulation Silencing METTL3 maintains normal cardiac function in response to hypertrophic stimuli through stress-response mechanism Dorn et al., 2019 2019 FTO Eraser Up-regulation Silencing FTO blunts hypertrophy of NRCM in response to α-adrenergic stimulation Kmietczyk et al., 2019 2019 2 Abnormal cardiac development METTL3/14 HuR Writer Down-regulation The level of METTL3 expression maintains and even improves the self-renewal capability of mESCs Wang et al., 2014 2014 FTO Eraser Mutation FTO plays an important role in early development of human central nervous and cardiovascular systems Daoud et al., 2016 2016 2 Obesity FTO Angptl4 Eraser Up-regulation FTO influences triglyceride metabolism in adipocytes and by post-transcriptional regulation of Angptl4 Wang et al., 2015 2015 YTHDF2 PPARγ / C/EBPα Reader Down-regulation Adipogenesis of porcine adipocytes can be led by a loss of m 6 A on FAM134B through m 6 A-YTHDF2-dependent way Cai et al., 2019 2019 Diabetes mellitus FTO FOXO1 / G6PC / DGAT2 Eraser Up-regulation FTO expression is highly related tothe impairment of plasma glucose and even multiple complications by altering target genes Yang et al., 2019 2019 Abnormal circadian rhythm METTL3 Per2 / Arntl Writer Down-regulation Silencing METTL3 can elicit circadian period elongation and RNA processing delay by distributing clock genes Per2 and Arntl Fustin et al., 2013 2013 Inflammation METTL3 MyD88S Writer Up-regulation Silencing METTL3 attenuates theinflammatory response via regulating MyD88S in LPS-induced hDPCs Liu et al., 2019 2019 Obesity 2 The improvement in the general standard of living has rendered obesity a sub-health symptom. Several clinical and basic research studies have shown that the increasing incidence and mortality of various CVDs and even cancers are closely associated with obesity, suggesting it contributes to the severe financial burden associated with the treatment of these conditions (Scuteri et al., 2007 2007 ; Koliaki et al., 2019 2019 ). In addition to dietary habits, the FTO gene, which is closely linked to obesity, was identified by the present study as a positive regulator of energy homeostasis, for example via lipid metabolism, by modulating m 6 A levels in RNA and DNA sequences in humans (Bartosovic et al., 2017 2017 ; Chen and Du, 2019 2019 ). The physiological and pathological development of obesity may be associated with FTO variants, which carry the at-risk alleles of single-nucleotide polymorphisms (SNPs), including rs9939609, rs8050136, rs3751812, rs7202116, and rs9930506, in the first intron of the FTO gene (Church et al., 2010 2010 ; Wang et al., 2015 2015 ). Variants of FTO were reported to have enhanced FTO expression and/or activity in previous study performed on homozygous individuals carrying the at-risk alleles (Church et al., 2010 2010 ). Moreover, most studies demonstrated that these at-risk SNPs appeared to promote energy intake and a preference for energy-dense foods (Cecil et al., 2008 2008 ; Speakman et al., 2008 2008 ; Timpson et al., 2008 2008 ; Haupt et al., 2009 2009 ), while in two independent genome-wide association studies, the FTO gene was shown to be a high risk factor contributing to early-onset and severe obesity of European and Indonesian subjects (Dina et al., 2007 2007 ; Daya et al., 2019 2019 ). An analysis of different phenotypes of mice has shown that adipocyte-specific FTO can play an important role in influencing triglyceride metabolism in adipocytes and consequently body weight. This is caused partly by post-transcriptional regulation of downstream genes, such as Angptl4 . This may decrease energy expenditure and promote fatty acid storage in adipose tissues, regardless of the intake from a high-fat or standard diet (Wang et al., 2015 2015 ). Furthermore, a loss of m 6 A on family with sequence similarity 134 member B (FAM134B) can lead to the adipogenesis of porcine adipocytes through the m 6 A-YTHDF2-dependent pathway (Cai et al., 2019 2019 ). The epigenetic modification of m 6 A can be a risk factor of CVDs related to obesity, although the exact molecular mechanism remains unclear. Diabetes mellitus 2 Pathoglycemia induced by diabetes mellitus, including hypoglycemia and hyperglycemia, has been identified to be the main risk factor contributing to CVDs and all-cause mortality in diabetic patients. In addition to controlling blood glucose, an increase in insulin sensitivity has become a new auxiliary or main treatment strategy of diabetes, notably in cases with insulin resistance (Khunti et al., 2015 2015 ; Abdul-Ghani et al., 2019 2019 ). Furthermore, hyperglycemia may lead to the down-regulation of m 6 A levels by enhancing the expression of FTO or other methyltransferases in patients with T2DM, suggesting an important epigenetic role of m 6 A in regulating glucose and lipid metabolism disorders (Gilbert and Liu, 2012 2012 ; Yang et al., 2019 2019 ). In addition to dysregulated oxidation of glucose, increased FTO expression induced by diabetes is highly associated with the impairment of plasma glucose and even multiple complications caused by altering the expression of target functional genes, such as forkhead box O1 ( FOXO1 ), glucose-6-phosphatase (G6Pase) catalytic subunit ( G6PC ), and diacylglycerol acyltransferase 2 ( DGAT2 ) (Souness et al., 1982 1982 ; Kursawe et al., 2016 2016 ; Li et al., 2017 2017 ; Yang et al., 2019 2019 ). Recently, it has been shown that an altered content of m 6 A can be used as a novel biomarker of T2DM since significantly lower levels of m 6 A are noted in both T2DM patients and diabetic rats. At present, FTO expression is the only indicator found to be positively correlated with the risk of diabetes by correlation analysis (Shen et al., 2015 2015 ). Nevertheless, whether m 6 A modification in diabetes mellitus is locus-specific remains to be elucidated. Abnormal circadian rhythm 2 Previous study has suggested that the circadian rhythm (day/night cycle) is one of the basic and vital features of the natural environment due to its contribution to the regulation of normal development and function of the cardiovascular system (Melkani and Panda, 2017 2017 ). It affects the expression of related genes and the levels of hormones associated with cardiac function, such as angiotensin II, renin, aldosterone, growth hormone, and atrial natriuretic peptide (McNamara et al., 2001 2001 ; Martino et al., 2004 2004 ; Martino and Sole, 2009 2009 ). Moreover, it has been suggested that the occurrence and the severity of certain CVDs are highly associated with the circadian rhythm via specific intrinsic mechanisms that are currently unknown (Mukamal et al., 2000 2000 ; Henriques et al., 2003 2003 ). The circadian clock may regulate metabolism in an epigenetic feedback loop by modifying the expression levels of certain genes coding for metabolic switches or other important components. This modification is caused at the level of transcription. The acetylation/deacetylation of histones occurs on the promoters related to protein complexes or on clock proteins directly. In addition to this process, methylation of histone proteins has been shown to play a vital role in maintaining the normal function of the circadian rhythm in vivo (Asher et al., 2008 2008 ; Nakahata et al., 2008 2008 ; Katada and Sassone-Corsi, 2010 2010 ). A recent study has shown that the transcriptional functions of several clock genes, such as period 2 ( Per2 ) and aryl hydrocarbon receptor nuclear translocator like ( Arntl ), play an important role in extending the circadian rhythm period by inhibiting the m 6 A modification of methylase METTL3, thereby promoting the uncoupling between steady-state pre-mRNA and cytoplasmic mRNA rhythm (Fustin et al., 2013 2013 ). It has also been predicted that the period of the circadian rhythm is positively associated with the efficiency of degradation and the nuclear import and export of Per2 mRNA, as determined by network model analysis (Wilkins et al., 2007 2007 ; Miki et al., 2012 2012 ). Moreover, Arntl is much more sensitive than Per2 with regard to the inhibition of METTL3 due to its higher mRNA nuclear accumulation and longer period of transcription (Fustin et al., 2013 2013 ). The decrease in RNA methylation induced by the pharmacological action of 3-deazaadenosine (3-DZA) might elongate the period of circadian rhythm in vivo and in vitro via the decreased hydrolysis of S -adenosylhomocysteine (SAH) (Fustin et al., 2013 2013 ; Singhal et al., 2013 2013 ; Lokody, 2014 2014 ). It has been suggested that m 6 A modification affects the circadian rhythm and may regulate cardiac function to a certain degree. Inflammation 2 CVDs and diabetes mellitus are defined as metabolic syndromes and have recently been investigated as chronic inflammatory diseases triggered by long-term stimulation of abnormal levels of plasma glucose, free fatty acids, and blood pressure. These abnormal biochemical profiles are promoted via the oxidative stress pathway and the interaction between the cytokines and the renin-angiotensin system (Wong et al., 2008 2008 ; Grandl and Wolfrum, 2018 2018 ; Fiechter et al., 2019 2019 ). Inflammation, including innate and adaptive immunity, is one of the major and fundamental risk factors of all stages of atherosclerosis (Weber and Noels, 2011 2011 ; Legein et al., 2015 2015 ; Ketelhuth et al., 2019 2019 ). Recent studies have shown that the pathological development of atherosclerosis is driven by immune reactions and is related mainly to immune effector mechanisms, which are involved in the infiltration and accumulation of lipoproteins in the arterial intima (Libby et al., 2011 2011 , 2013 2013 ; Ketelhuth and Hansson, 2016 2016 ). In addition to the epigenetic regulation of SNPs that is related to different degrees of CVD risks, hyperacetylation at the 27th lysine residue of the histone H3 protein (H3K27ac) is linked to lower expression of proinflammatory genes in the reversible process of inflammation and aging. This may also explain certain unclear mechanisms in the link between inflammation and the progression of CVDs (Smith and Humphries, 2009 2009 ; IL6R Genetics Consortium Emerging Risk Factors Collaboration, 2012 2012 ; Xuan et al., 2016 2016 ; Mitrokhin et al., 2017 2017 ; Cheng et al., 2018 2018 ). Furthermore, telomere shortening and modulation of certain microRNAs associated with DNA damage are considered another epigenetic mechanism accounting for inflammation, since they can promote the secretion of proinflammatory cytokines through several proinflammatory pathways (Olivieri et al., 2015 2015 ). Since the specific mechanism of the association between inflammation and atherosclerosis has not been fully clarified, m 6 A has become a new focus for the development of novel clinical therapeutic strategies against CVD. Recent studies have demonstrated that the loss of N 6 -adenosine methyltransferase METTL3 can attenuate the increased expression levels of several inflammatory cytokines and various genes associated with the inflammatory response, mainly by changing the phosphorylation levels of related signaling pathways and by regulating the mRNA splicing of splice variant of myeloid differentiation factor 88 (MyD88S) in lipopolysaccharide (LPS)-induced human dental pulp cells (HDPCs). This suggests the possible role of epitranscriptomic modification of m 6 A during the process of inflammation in pathophysiological mechanisms leading to CVDs (Feng et al., 2018 2018 ). Conclusions 1 Several independent studies have confirmed that the continuous and dynamic regulation of m 6 A in different internal biological metabolic processes has a profound impact on modulating the expression of cardiac genes in the pathological development of CVDs. Moreover, these risk factors can be combined with several other environmental factors that affect the development of these diseases. This occurs by regulation of RNA transcription, splicing, processing, translation, and decay (Niu et al., 2013 2013 ; Guo et al., 2017 2017 ; Roignant and Soller, 2017 2017 ; Wei et al., 2017 2017 ). Therefore, certain m 6 A enzymes, including FTO and METTL3, have been shown to control epitranscriptomic regulation of specific cardiac defects caused by distinct mechanisms. However, the possible association between m 6 A and other CVDs and even between cardiovascular-associated diseases, such as high blood pressure and congenital heart disease, remains unexplored. Although the use of specific inhibitors in different models of animals or cardiocytes has established the cardioprotective role of RNA-modifying enzymes in m 6 A modification, additional therapeutic agents for CVDs should be assessed in future studies. References MA Abdul-Ghani , A Jayyousi , RA Defronzo , 等 . Insulin resistance the link between T2DM and CVD: basic mechanisms and clinical implications . Curr Vasc Pharmacol , 2019 . 17 ( 2 ): 153 - 163 . 29032755 DOI: 10.2174/1570161115666171010115119 http://doi.org/10.2174/1570161115666171010115119 . Insulin resistance the link between T2DM and CVD: basic mechanisms and clinical implications G Asher , D Gatfield , M Stratmann , 等 . Sirt1 regulates circadian clock gene expression through PER2 deacetylation . Cell , 2008 . 134 ( 2 ): 317 - 328 . 18662546 DOI: 10.1016/j.cell.2008.06.050 http://doi.org/10.1016/j.cell.2008.06.050 . Sirt1 regulates circadian clock gene expression through PER2 deacetylation M Bartosovic , HC Molares , P Gregorova , 等 . N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3'-end processing . Nucleic Acids Res , 2017 . 45 ( 19 ): 11356 - 11370 . 28977517 DOI: 10.1093/nar/gkx778 http://doi.org/10.1093/nar/gkx778 . N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3'-end processing D Bayarsaihan . Epigenetic mechanisms in inflammation . J Dent Res , 2011 . 90 ( 1 ): 9 - 17 . 21178119 DOI: 10.1177/0022034510378683 http://doi.org/10.1177/0022034510378683 . Epigenetic mechanisms in inflammation L Bochmann , P Sarathchandra , F Mori , 等 . Revealing new mouse epicardial cell markers through transcriptomics . PLoS ONE , 2010 . 5 ( 6 ): e11429 20596535 DOI: 10.1371/journal.pone.0011429 http://doi.org/10.1371/journal.pone.0011429 . Revealing new mouse epicardial cell markers through transcriptomics S Boissel , O Reish , K Proulx , 等 . Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations . Am J Hum Genet , 2009 . 85 ( 1 ): 106 - 111 . 19559399 DOI: 10.1016/j.ajhg.2009.06.002 http://doi.org/10.1016/j.ajhg.2009.06.002 . Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations I Buysschaert , T Schmidt , C Roncal , 等 . Genetics, epigenetics and pharmaco-(epi)genomics in angiogenesis . J Cell Mol Med , 2008 . 12 ( 6b ): 2533 - 2551 . 19210754 DOI: 10.1111/j.1582-4934.2008.00515.x http://doi.org/10.1111/j.1582-4934.2008.00515.x . Genetics, epigenetics and pharmaco-(epi)genomics in angiogenesis CL Cai , JC Martin , YF Sun , 等 . A myocardial lineage derives from Tbx18 epicardial cells . Nature , 2008 . 454 ( 7200 ): 104 - 108 . 18480752 DOI: 10.1038/nature06969 http://doi.org/10.1038/nature06969 . A myocardial lineage derives from Tbx18 epicardial cells M Cai , Q Liu , Q Jiang , 等 . Loss of m 6 A on FAM134B promotes adipogenesis in porcine adipocytes through m 6 A-YTHDF2-dependent way . IUBMB Life , 2019 . 71 ( 5 ): 580 - 586 . 30506811 DOI: 10.1002/iub.1974 http://doi.org/10.1002/iub.1974 . Loss of m6A on FAM134B promotes adipogenesis in porcine adipocytes through m6A-YTHDF2-dependent way V Calvanese , MF Fraga . Epigenetics of embryonic stem cells . Adv Exp Med Biol , 2012 . 741 231 - 253 . 22457114 DOI: 10.1007/978-1-4614-2098-9_16 http://doi.org/10.1007/978-1-4614-2098-9_16 . Epigenetics of embryonic stem cells L Carnevali , G Graiani , S Rossi , 等 . Signs of cardiac autonomic imbalance and proarrhythmic remodeling in FTO deficient mice . PLoS ONE , 2014 . 9 ( 4 ): e95499 24743632 DOI: 10.1371/journal.pone.0095499 http://doi.org/10.1371/journal.pone.0095499 . Signs of cardiac autonomic imbalance and proarrhythmic remodeling in FTO deficient mice JE Cecil , R Tavendale , P Watt , 等 . An obesity-associated FTO gene variant and increased energy intake in children . N Engl J Med , 2008 . 359 ( 24 ): 2558 - 2566 . 19073975 DOI: 10.1056/NEJMoa0803839 http://doi.org/10.1056/NEJMoa0803839 . An obesity-associated FTO gene variant and increased energy intake in children JL Chen , B Du . Novel positioning from obesity to cancer: FTO, an m 6 A RNA demethylase, regulates tumour progression . J Cancer Res Clin Oncol , 2019 . 145 ( 1 ): 19 - 29 . 30465076 DOI: 10.1007/s00432-018-2796-0 http://doi.org/10.1007/s00432-018-2796-0 . Novel positioning from obesity to cancer: FTO, an m6A RNA demethylase, regulates tumour progression H Cheng , HW Xuan , CD Green , 等 . Repression of human and mouse brain inflammaging transcriptome by broad gene-body histone hyperacetylation . Proc Natl Acad Sci USA , 2018 . 115 ( 29 ): 7611 - 7616 . DOI: 10.1073/pnas.1800656115 http://doi.org/10.1073/pnas.1800656115 . Repression of human and mouse brain inflammaging transcriptome by broad gene-body histone hyperacetylation C Church , L Moir , F McMurray , 等 . Overexpression of Fto leads to increased food intake and results in obesity . Nat Genet , 2010 . 42 ( 12 ): 1086 - 1092 . 21076408 DOI: 10.1038/ng.713 http://doi.org/10.1038/ng.713 . Overexpression of Fto leads to increased food intake and results in obesity MA Cole , AHA Jamil , LC Heather , 等 . On the pivotal role of PPARα in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury . FASEB J , 2016 . 30 ( 8 ): 2684 - 2697 . 27103577 DOI: 10.1096/fj.201500094R http://doi.org/10.1096/fj.201500094R . On the pivotal role of PPARα in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury KE Cosselman , A Navas-Acien , JD Kaufman . Environmental factors in cardiovascular disease . Nat Rev Cardiol , 2015 . 12 ( 11 ): 627 - 642 . 26461967 DOI: 10.1038/nrcardio.2015.152 http://doi.org/10.1038/nrcardio.2015.152 . Environmental factors in cardiovascular disease M da Luz Sousa Fialho , AHA Jamil , GA Stannard , 等 . Hypoxia-inducible factor 1 signalling, metabolism and its therapeutic potential in cardiovascular disease . Biochim Biophys Acta Mol Basis Dis , 2019 . 1865 ( 4 ): 831 - 843 . 30266651 DOI: 10.1016/j.bbadis.2018.09.024 http://doi.org/10.1016/j.bbadis.2018.09.024 . Hypoxia-inducible factor 1 signalling, metabolism and its therapeutic potential in cardiovascular disease CV Dang , GL Semenza . Oncogenic alterations of metabolism . Trends Biochem Sci , 1999 . 24 ( 2 ): 68 - 72 . 10098401 . Oncogenic alterations of metabolism H Daoud , D Zhang , F McMurray , 等 . Identification of a pathogenic FTO mutation by next-generation sequencing in a newborn with growth retardation and developmental delay . J Med Genet , 2016 . 53 ( 3 ): 200 - 207 . 26378117 DOI: 10.1136/jmedgenet-2015-103399 http://doi.org/10.1136/jmedgenet-2015-103399 . Identification of a pathogenic FTO mutation by next-generation sequencing in a newborn with growth retardation and developmental delay M Daya , DA Pujianto , F Witjaksono , 等 . Obesity risk and preference for high dietary fat intake are determined by FTO rs9939609 gene polymorphism in selected Indonesian adults . Asia Pac J Clin Nutr , 2019 . 28 ( 1 ): 183 - 191 . 30896430 DOI: 10.6133/apjcn.201903_28(1).0024 http://doi.org/10.6133/apjcn.201903_28(1).0024 . Obesity risk and preference for high dietary fat intake are determined by FTO rs9939609 gene polymorphism in selected Indonesian adults C Dina , D Meyre , S Gallina , 等 . Variation in FTO contributes to childhood obesity and severe adult obesity . Nat Genet , 2007 . 39 ( 6 ): 724 - 726 . 17496892 DOI: 10.1038/ng2048 http://doi.org/10.1038/ng2048 . Variation in FTO contributes to childhood obesity and severe adult obesity D Dominissini , S Moshitch-Moshkovitz , S Schwartz , 等 . Topology of the human and mouse m 6 A RNA methylomes revealed by m 6 A-seq . Nature , 2012 . 485 ( 7397 ): 201 - 206 . 22575960 DOI: 10.1038/nature11112 http://doi.org/10.1038/nature11112 . Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq LE Dorn , L Lasman , J Chen , 等 . The N 6 -methyladenosine mRNA methylase METTL3 controls cardiac homeostasis and hypertrophy . Circulation , 2019 . 139 ( 4 ): 533 - 545 . 30586742 DOI: 10.1161/circulationaha.118.036146 http://doi.org/10.1161/circulationaha.118.036146 . The N6-methyladenosine mRNA methylase METTL3 controls cardiac homeostasis and hypertrophy H el Azzouzi , S Leptidis , E Dirkx , 等 . The hypoxia-inducible microRNA cluster miR-199a~214 targets myocardial PPARδ and impairs mitochondrial fatty acid oxidation . Cell Metab , 2013 . 18 ( 3 ): 341 - 354 . 24011070 DOI: 10.1016/j.cmet.2013.08.009 http://doi.org/10.1016/j.cmet.2013.08.009 . The hypoxia-inducible microRNA cluster miR-199a~214 targets myocardial PPARδ and impairs mitochondrial fatty acid oxidation MF Essop . Cardiac metabolic adaptations in response to chronic hypoxia . J Physiol , 2007 . 584 ( 3 ): 715 - 726 . 17761770 DOI: 10.1113/jphysiol.2007.143511 http://doi.org/10.1113/jphysiol.2007.143511 . Cardiac metabolic adaptations in response to chronic hypoxia BI Fedeles , V Singh , JC Delaney , 等 . The AlkB family of Fe(II)/α-ketoglutarate-dependent dioxygenases: repairing nucleic acid alkylation damage and beyond . J Biol Chem , 2015 . 290 ( 34 ): 20734 - 20742 . 26152727 DOI: 10.1074/jbc.R115.656462 http://doi.org/10.1074/jbc.R115.656462 . The AlkB family of Fe(II)/α-ketoglutarate-dependent dioxygenases: repairing nucleic acid alkylation damage and beyond ZH Feng , QM Li , RS Meng , 等 . METTL3 regulates alternative splicing of MyD88 upon the lipopolysaccharide-induced inflammatory response in human dental pulp cells . J Cell Mol Med , 2018 . 22 ( 5 ): 2558 - 2568 . 29502358 DOI: 10.1111/jcmm.13491 http://doi.org/10.1111/jcmm.13491 . METTL3 regulates alternative splicing of MyD88 upon the lipopolysaccharide-induced inflammatory response in human dental pulp cells JL Fernández-Morera , V Calvanese , S Rodríguez-Rodero , 等 . Epigenetic regulation of the immune system in health and disease . Tissue Antigens , 2010 . 76 ( 6 ): 431 - 439 . 21058938 DOI: 10.1111/j.1399-0039.2010.01587.x http://doi.org/10.1111/j.1399-0039.2010.01587.x . Epigenetic regulation of the immune system in health and disease M Fiechter , A Haider , S Bengs , 等 . Sex differences in the association between inflammation and ischemic heart disease . Thromb Haemost , 2019 . 119 ( 9 ): 1471 - 1480 . 31226718 DOI: 10.1055/s-0039-1692442 http://doi.org/10.1055/s-0039-1692442 . Sex differences in the association between inflammation and ischemic heart disease Y Fu , D Dominissini , G Rechavi , 等 . Gene expression regulation mediated through reversible m 6 A RNA methylation . Nat Rev Genet , 2014 . 15 ( 5 ): 293 - 306 . 24662220 DOI: 10.1038/nrg3724 http://doi.org/10.1038/nrg3724 . Gene expression regulation mediated through reversible m6A RNA methylation JM Fustin , M Doi , Y Yamaguchi , 等 . RNA-methylation-dependent RNA processing controls the speed of the circadian clock . Cell , 2013 . 155 ( 4 ): 793 - 806 . 24209618 DOI: 10.1016/j.cell.2013.10.026 http://doi.org/10.1016/j.cell.2013.10.026 . RNA-methylation-dependent RNA processing controls the speed of the circadian clock HL Gan , L Hong , FL Yang , 等 . Progress in epigenetic modification of mRNA and the function of m 6 A modification . Chin J Biotechnol , 2019 . 35 ( 5 ): 775 - 783 . (in Chinese) . Progress in epigenetic modification of mRNA and the function of m6A modification L Ge , Y Cai , F Ying , 等 . miR-181c-5p exacerbates hypoxia/reoxygenation-induced cardiomyocyte apoptosis via targeting PTPN4 . Oxid Med Cell Longev, 2019: 1957920 , 2019 . DOI: 10.1155/2019/1957920 http://doi.org/10.1155/2019/1957920 . miR-181c-5p exacerbates hypoxia/reoxygenation-induced cardiomyocyte apoptosis via targeting PTPN4 T Gerken , CA Girard , YCL Tung , 等 . The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase . Science , 2007 . 318 ( 5855 ): 1469 - 1472 . 17991826 DOI: 10.1126/science.1151710 http://doi.org/10.1126/science.1151710 . The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase ER Gibney , CM Nolan . Epigenetics and gene expression . Heredity (Edinb) , 2010 . 105 ( 1 ): 4 - 13 . 20461105 DOI: 10.1038/hdy.2010.54 http://doi.org/10.1038/hdy.2010.54 . Epigenetics and gene expression ER Gilbert , DM Liu . Epigenetics: the missing link to understanding β-cell dysfunction in the pathogenesis of type 2 diabetes . Epigenetics , 2012 . 7 ( 8 ): 841 - 852 . 22810088 DOI: 10.4161/epi.21238 http://doi.org/10.4161/epi.21238 . Epigenetics: the missing link to understanding β-cell dysfunction in the pathogenesis of type 2 diabetes G Grandl , C Wolfrum . Hemostasis, endothelial stress, inflammation, and the metabolic syndrome . Semin Immunopathol , 2018 . 40 ( 2 ): 215 - 224 . 29209827 DOI: 10.1007/s00281-017-0666-5 http://doi.org/10.1007/s00281-017-0666-5 . Hemostasis, endothelial stress, inflammation, and the metabolic syndrome MJ Guo , XH Liu , XT Zheng , 等 . m 6 A RNA modification determines cell fate by regulating mRNA degradation . Cell Reprogram , 2017 . 19 ( 4 ): 225 - 231 . 28682669 DOI: 10.1089/cell.2016.0041 http://doi.org/10.1089/cell.2016.0041 . m6A RNA modification determines cell fate by regulating mRNA degradation J Gustavsson , K Mehlig , K Leander , 等 . FTO genotype, physical activity, and coronary heart disease risk in Swedish men and women . Circ Cardiovasc Genet , 2014 . 7 ( 2 ): 171 - 177 . 24622111 DOI: 10.1161/circgenetics.111.000007 http://doi.org/10.1161/circgenetics.111.000007 . FTO genotype, physical activity, and coronary heart disease risk in Swedish men and women A Haupt , C Thamer , H Staiger , 等 . Variation in the FTO gene influences food intake but not energy expenditure . Exp Clin Endocrinol Diabetes , 2009 . 117 ( 4 ): 194 - 197 . 19053021 DOI: 10.1055/s-0028-1087176 http://doi.org/10.1055/s-0028-1087176 . Variation in the FTO gene influences food intake but not energy expenditure C He . Grand challenge commentary: RNA epigenetics? . Nat Chem Biol , 2010 . 6 ( 12 ): 863 - 865 . 21079590 DOI: 10.1038/nchembio.482 http://doi.org/10.1038/nchembio.482 . Grand challenge commentary: RNA epigenetics? SK He , XH Li , N Chan , 等 . Review: epigenetic mechanisms in ocular disease . Mol Vis , 2013 . 19 665 - 674 . 23559860 . Review: epigenetic mechanisms in ocular disease JPS Henriques , AP Haasdijk , F Zijlstra , 等 . Outcome of primary angioplasty for acute myocardial infarction during routine duty hours versus during off-hours . J Am Coll Cardiol , 2003 . 41 ( 12 ): 2138 - 2142 . 12821237 DOI: 10.1016/S0735-1097(03)00461-3 http://doi.org/10.1016/S0735-1097(03)00461-3 . Outcome of primary angioplasty for acute myocardial infarction during routine duty hours versus during off-hours ME Hess , S Hess , KD Meyer , 等 . The fat mass and obesity associated gene ( Fto ) regulates activity of the dopaminergic midbrain circuitry . Nat Neurosci , 2013 . 16 ( 8 ): 1042 - 1048 . 23817550 DOI: 10.1038/nn.3449 http://doi.org/10.1038/nn.3449 . The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry N Hou , Y Wen , X Yuan , 等 . Activation of Yap1/Taz signaling in ischemic heart disease and dilated cardiomyopathy . Exp Mol Pathol , 2017 . 103 ( 3 ): 267 - 275 . 29154888 DOI: 10.1016/j.yexmp.2017.11.006 http://doi.org/10.1016/j.yexmp.2017.11.006 . Activation of Yap1/Taz signaling in ischemic heart disease and dilated cardiomyopathy Genetics Consortium IL6R , Factors Collaboration Emerging Risk , 等 . Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies . Lancet , 2012 . 379 ( 9822 ): 1205 - 1213 . 22421339 DOI: 10.1016/s0140-6736(11)61931-4 http://doi.org/10.1016/s0140-6736(11)61931-4 . Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies B Iyen , N Qureshi , J Kai , 等 . Risk of cardiovascular disease outcomes in primary care subjects with familial hypercholesterolaemia: a cohort study . Atherosclerosis , 2019 . 287 8 - 15 . 31181417 DOI: 10.1016/j.atherosclerosis.2019.05.017 http://doi.org/10.1016/j.atherosclerosis.2019.05.017 . Risk of cardiovascular disease outcomes in primary care subjects with familial hypercholesterolaemia: a cohort study K James , LRB Weitzel , CD Engelman , 等 . Genome scan linkage results for longitudinal systolic blood pressure phenotypes in subjects from the Framingham Heart Study . BMC Genet, 4:S83 , 2003 . DOI: 10.1186/1471-2156-4-s1-s83 http://doi.org/10.1186/1471-2156-4-s1-s83 . Genome scan linkage results for longitudinal systolic blood pressure phenotypes in subjects from the Framingham Heart Study GF Jia , Y Fu , X Zhao , 等 . N 6 -methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO . Nat Chem Biol , 2011 . 7 ( 12 ): 885 - 887 . 22002720 DOI: 10.1038/nchembio.687 http://doi.org/10.1038/nchembio.687 . N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO J Jin , YF Liu , LH Huang , 等 . Advances in epigenetic regulation of vascular aging . Rev Cardiovasc Med , 2019 . 20 ( 1 ): 19 - 25 . 31184092 . Advances in epigenetic regulation of vascular aging S Katada , P Sassone-Corsi . The histone methyltransferase MLL1 permits the oscillation of circadian gene expression . Nat Struct Mol Biol , 2010 . 17 ( 12 ): 1414 - 1421 . 21113167 DOI: 10.1038/nsmb.1961 http://doi.org/10.1038/nsmb.1961 . The histone methyltransferase MLL1 permits the oscillation of circadian gene expression EM Kennedy , HP Bogerd , AVR Kornepati , 等 . Posttranscriptional m 6 A editing of HIV-1 mRNAs enhances viral gene expression . Cell Host Microbe , 2016 . 19 ( 5 ): 675 - 685 . 27117054 DOI: 10.1016/j.chom.2016.04.002 http://doi.org/10.1016/j.chom.2016.04.002 . Posttranscriptional m6A editing of HIV-1 mRNAs enhances viral gene expression DFJ Ketelhuth , GK Hansson . Adaptive response of T and B cells in atherosclerosis . Circ Res , 2016 . 118 ( 4 ): 668 - 678 . 26892965 DOI: 10.1161/circresaha.115.306427 http://doi.org/10.1161/circresaha.115.306427 . Adaptive response of T and B cells in atherosclerosis DFJ Ketelhuth , E Lutgens , M Bäck , 等 . Immunometabolism and atherosclerosis: perspectives and clinical significance: a position paper from the Working Group on Atherosclerosis and Vascular Biology of the European Society of Cardiology . Cardiovasc Res , 2019 . 115 ( 9 ): 1385 - 1392 . 31228191 DOI: 10.1093/cvr/cvz166 http://doi.org/10.1093/cvr/cvz166 . Immunometabolism and atherosclerosis: perspectives and clinical significance: a position paper from the Working Group on Atherosclerosis and Vascular Biology of the European Society of Cardiology K Khunti , M Davies , A Majeed , 等 . Hypoglycemia and risk of cardiovascular disease and all-cause mortality in insulin-treated people with type 1 and type 2 diabetes: a cohort study . Diabetes Care , 2015 . 38 ( 2 ): 316 - 322 . 25492401 DOI: 10.2337/dc14-0920 http://doi.org/10.2337/dc14-0920 . Hypoglycemia and risk of cardiovascular disease and all-cause mortality in insulin-treated people with type 1 and type 2 diabetes: a cohort study V Kmietczyk , E Riechert , L Kalinski , 等 . m 6 A-mRNA methylation regulates cardiac gene expression and cellular growth . Life Sci Alliance , 2019 . 2 ( 2 ): e201800233 . m6A-mRNA methylation regulates cardiac gene expression and cellular growth C Koliaki , S Liatis , A Kokkinos . Obesity and cardiovascular disease: revisiting an old relationship . Metabolism , 2019 . 92 98 - 107 . 30399375 DOI: 10.1016/j.metabol.2018.10.011 http://doi.org/10.1016/j.metabol.2018.10.011 . Obesity and cardiovascular disease: revisiting an old relationship R Kursawe , VD Dixit , PE Scherer , 等 . A role of the inflammasome in the low storage capacity of the abdominal subcutaneous adipose tissue in obese adolescents . Diabetes , 2016 . 65 ( 3 ): 610 - 618 . 26718495 DOI: 10.2337/db15-1478 http://doi.org/10.2337/db15-1478 . A role of the inflammasome in the low storage capacity of the abdominal subcutaneous adipose tissue in obese adolescents SH Lee , PL Wolf , R Escudero , 等 . Early expression of angiogenesis factors in acute myocardial ischemia and infarction . N Engl J Med , 2000 . 342 ( 9 ): 626 - 633 . 10699162 DOI: 10.1056/nejm200003023420904 http://doi.org/10.1056/nejm200003023420904 . Early expression of angiogenesis factors in acute myocardial ischemia and infarction B Legein , EM Janssen , TL Theelen , 等 . Ablation of CD8α + dendritic cell mediated cross-presentation does not impact atherosclerosis in hyperlipidemic mice . Sci Rep, 5:15414 , 2015 . DOI: 10.1038/srep15414 http://doi.org/10.1038/srep15414 . Ablation of CD8α+ dendritic cell mediated cross-presentation does not impact atherosclerosis in hyperlipidemic mice Y Li , ZQ Ma , S Jiang , 等 . A global perspective on FOXO1 in lipid metabolism and lipid-related diseases . Prog Lipid Res , 2017 . 66 42 - 49 . 28392404 DOI: 10.1016/j.plipres.2017.04.002 http://doi.org/10.1016/j.plipres.2017.04.002 . A global perspective on FOXO1 in lipid metabolism and lipid-related diseases P Libby , PM Ridker , GK Hansson . Progress and challenges in translating the biology of atherosclerosis . Nature , 2011 . 473 ( 7347 ): 317 - 325 . 21593864 DOI: 10.1038/nature10146 http://doi.org/10.1038/nature10146 . Progress and challenges in translating the biology of atherosclerosis P Libby , AH Lichtman , GK Hansson . Immune effector mechanisms implicated in atherosclerosis: from mice to humans . Immunity , 2013 . 38 ( 6 ): 1092 - 1104 . 23809160 DOI: 10.1016/j.immuni.2013.06.009 http://doi.org/10.1016/j.immuni.2013.06.009 . Immune effector mechanisms implicated in atherosclerosis: from mice to humans SB Lin , J Choe , P Du , 等 . The m 6 A methyltransferase METTL3 promotes translation in human cancer cells . Mol Cell , 2016 . 62 ( 3 ): 335 - 345 . 27117702 DOI: 10.1016/j.molcel.2016.03.021 http://doi.org/10.1016/j.molcel.2016.03.021 . The m6A methyltransferase METTL3 promotes translation in human cancer cells JZ Liu , YN Yue , DL Han , 等 . A METTL3–METTL14 complex mediates mammalian nuclear RNA N 6 -adenosine methylation . Nat Chem Biol , 2014 . 10 ( 2 ): 93 - 95 . 24316715 DOI: 10.1038/nchembio.1432 http://doi.org/10.1038/nchembio.1432 . A METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation N Liu , T Pan . RNA epigenetics . Transl Res , 2015 . 165 ( 1 ): 28 - 35 . 24768686 DOI: 10.1016/j.trsl.2014.04.003 http://doi.org/10.1016/j.trsl.2014.04.003 . RNA epigenetics X Liu , L Lin , Q Li , 等 . ERK1/2 communicates GPCR and EGFR signaling pathways to promote CTGF-mediated hypertrophic cardiomyopathy upon Ang-II stimulation . BMC Mol Cell Biol, 20:14 , 2019 . DOI: 10.1186/s12860-019-0202-7 http://doi.org/10.1186/s12860-019-0202-7 . ERK1/2 communicates GPCR and EGFR signaling pathways to promote CTGF-mediated hypertrophic cardiomyopathy upon Ang-II stimulation I Lokody . Gene regulation: RNA methylation regulates the circadian clock . Nat Rev Genet , 2014 . 15 ( 1 ): 3 24281145 DOI: 10.1038/nrg3638 http://doi.org/10.1038/nrg3638 . Gene regulation: RNA methylation regulates the circadian clock L Lu , M Liu , RR Sun , 等 . Myocardial infarction: symptoms and treatments . Cell Biochem Biophys , 2015 . 72 ( 3 ): 865 - 867 . 25638347 DOI: 10.1007/s12013-015-0553-4 http://doi.org/10.1007/s12013-015-0553-4 . Myocardial infarction: symptoms and treatments T Martino , S Arab , M Straume , 等 . Day/night rhythms in gene expression of the normal murine heart . J Mol Med (Berl) , 2004 . 82 ( 4 ): 256 - 264 . 14985853 DOI: 10.1007/s00109-003-0520-1 http://doi.org/10.1007/s00109-003-0520-1 . Day/night rhythms in gene expression of the normal murine heart TA Martino , MJ Sole . Molecular time: an often overlooked dimension to cardiovascular disease . Circ Res , 2009 . 105 ( 11 ): 1047 - 1061 . 19926881 DOI: 10.1161/circresaha.109.206201 http://doi.org/10.1161/circresaha.109.206201 . Molecular time: an often overlooked dimension to cardiovascular disease P Mathiyalagan , M Adamiak , J Mayourian , 等 . FTO-dependent N 6 -methyladenosine regulates cardiac function during remodeling and repair . Circulation , 2019 . 139 ( 4 ): 518 - 532 . 29997116 DOI: 10.1161/circulationaha.118.033794 http://doi.org/10.1161/circulationaha.118.033794 . FTO-dependent N6-methyladenosine regulates cardiac function during remodeling and repair J Mauer , XB Luo , A Blanjoie , 等 . Reversible methylation of m 6 A m in the 5' cap controls mRNA stability . Nature , 2017 . 541 ( 7637 ): 371 - 375 . 28002401 DOI: 10.1038/nature21022 http://doi.org/10.1038/nature21022 . Reversible methylation of m6Am in the 5' cap controls mRNA stability EA Mazzio , KFA Soliman . Basic concepts of epigenetics: impact of environmental signals on gene expression . Epigenetics , 2012 . 7 ( 2 ): 119 - 130 . 22395460 DOI: 10.4161/epi.7.2.18764 http://doi.org/10.4161/epi.7.2.18764 . Basic concepts of epigenetics: impact of environmental signals on gene expression P McNamara , SB Seo , RD Rudic , 等 . Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock . Cell , 2001 . 105 ( 7 ): 877 - 889 . 11439184 DOI: 10.1016/S0092-8674(01)00401-9 http://doi.org/10.1016/S0092-8674(01)00401-9 . Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock GC Melkani , S Panda . Time-restricted feeding for prevention and treatment of cardiometabolic disorders . J Physiol , 2017 . 595 ( 12 ): 3691 - 3700 . 28295377 DOI: 10.1113/jp273094 http://doi.org/10.1113/jp273094 . Time-restricted feeding for prevention and treatment of cardiometabolic disorders KD Meyer , Y Saletore , P Zumbo , 等 . Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons . Cell , 2012 . 149 ( 7 ): 1635 - 1646 . 22608085 DOI: 10.1016/j.cell.2012.05.003 http://doi.org/10.1016/j.cell.2012.05.003 . Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons KD Meyer , DP Patil , J Zhou , 等 . 5' UTR m 6 A promotes cap-independent translation . Cell , 2015 . 163 ( 4 ): 999 - 1010 . 26593424 DOI: 10.1016/j.cell.2015.10.012 http://doi.org/10.1016/j.cell.2015.10.012 . 5' UTR m6A promotes cap-independent translation T Miki , ZX Xu , M Chen-Goodspeed , 等 . PML regulates PER2 nuclear localization and circadian function . EMBO J , 2012 . 31 ( 6 ): 1427 - 1439 . 22274616 DOI: 10.1038/emboj.2012.1 http://doi.org/10.1038/emboj.2012.1 . PML regulates PER2 nuclear localization and circadian function V Mitrokhin , A Nikitin , O Brovkina , 等 . Association between interleukin-6/6R gene polymorphisms and coronary artery disease in Russian population: influence of interleukin-6/6R gene polymorphisms on inflammatory markers . J Inflamm Res , 2017 . 10 151 - 160 . 29042807 DOI: 10.2147/jir.s141682 http://doi.org/10.2147/jir.s141682 . Association between interleukin-6/6R gene polymorphisms and coronary artery disease in Russian population: influence of interleukin-6/6R gene polymorphisms on inflammatory markers KJ Mukamal , JE Muller , M Maclure , 等 . Increased risk of congestive heart failure among infarctions with nighttime onset . Am Heart J , 2000 . 140 ( 3 ): 438 - 442 . 10966545 DOI: 10.1067/mhj.2000.108830 http://doi.org/10.1067/mhj.2000.108830 . Increased risk of congestive heart failure among infarctions with nighttime onset Y Nakahata , M Kaluzova , B Grimaldi , 等 . The NAD + -dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control . Cell , 2008 . 134 ( 2 ): 329 - 340 . 18662547 DOI: 10.1016/j.cell.2008.07.002 http://doi.org/10.1016/j.cell.2008.07.002 . The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control YM Niu , X Zhao , YS Wu , 等 . N 6 -methyl-adenosine (m 6 A) in RNA: an old modification with a novel epigenetic function . Genomics Proteomics Bioinformatics , 2013 . 11 ( 1 ): 8 - 17 . 23453015 DOI: 10.1016/j.gpb.2012.12.002 http://doi.org/10.1016/j.gpb.2012.12.002 . N6-methyl-adenosine (m6A) in RNA: an old modification with a novel epigenetic function F Olivieri , MC Albertini , M Orciani , 等 . DNA damage response (DDR) and senescence: shuttled inflamma-miRNAs on the stage of inflammaging . Oncotarget , 2015 . 6 ( 34 ): 35509 - 35521 . 26431329 . DNA damage response (DDR) and senescence: shuttled inflamma-miRNAs on the stage of inflammaging A Ortiz-Barahona , D Villar , N Pescador , 等 . Genome-wide identification of hypoxia-inducible factor binding sites and target genes by a probabilistic model integrating transcription-profiling data and in silico binding site prediction . Nucleic Acids Res , 2010 . 38 ( 7 ): 2332 - 2345 . 20061373 DOI: 10.1093/nar/gkp1205 http://doi.org/10.1093/nar/gkp1205 . Genome-wide identification of hypoxia-inducible factor binding sites and target genes by a probabilistic model integrating transcription-profiling data and in silico binding site prediction S Panneerdoss , VK Eedunuri , P Yadav , 等 . Cross-talk among writers, readers, and erasers of m 6 A regulates cancer growth and progression . Sci Adv , 2018 . 4 ( 10 ): eaar8263 30306128 DOI: 10.1126/sciadv.aar8263 http://doi.org/10.1126/sciadv.aar8263 . Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression NC Parashar , G Parashar , H Nayyar , 等 . N 6 -adenine DNA methylation demystified in eukaryotic genome: from biology to pathology . Biochimie , 2018 . 144 56 - 62 . 29074394 DOI: 10.1016/j.biochi.2017.10.014 http://doi.org/10.1016/j.biochi.2017.10.014 . N6-adenine DNA methylation demystified in eukaryotic genome: from biology to pathology N Pastore , OA Brady , HI Diab , 等 . TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages . Autophagy , 2016 . 12 ( 8 ): 1240 - 1258 . 27171064 DOI: 10.1080/15548627.2016.1179405 http://doi.org/10.1080/15548627.2016.1179405 . TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages DP Patil , BF Pickering , SR Jaffrey . Reading m 6 A in the transcriptome: m 6 A-binding proteins . Trends Cell Biol , 2018 . 28 ( 2 ): 113 - 127 . 29103884 DOI: 10.1016/j.tcb.2017.10.001 http://doi.org/10.1016/j.tcb.2017.10.001 . Reading m6A in the transcriptome: m6A-binding proteins MSB Peña , A Rollins . Environmental exposures and cardiovascular disease: a challenge for health and development in low-and middle-income countries . Cardiol Clin , 2017 . 35 ( 1 ): 71 - 86 . 27886791 DOI: 10.1016/j.ccl.2016.09.001 http://doi.org/10.1016/j.ccl.2016.09.001 . Environmental exposures and cardiovascular disease: a challenge for health and development in low-and middle-income countries DE Reese , T Mikawa , DM Bader . Development of the coronary vessel system . Circ Res , 2002 . 91 ( 9 ): 761 - 768 . 12411389 DOI: 10.1161/01.RES.0000038961.53759.3C http://doi.org/10.1161/01.RES.0000038961.53759.3C . Development of the coronary vessel system H Rodriguez , R Drouin , GP Holmquist , 等 . A hot spot for hydrogen peroxide-induced damage in the human hypoxia-inducible factor 1 binding site of the PGK 1 gene . Arch Biochem Biophys , 1997 . 338 ( 2 ): 207 - 212 . 9028873 DOI: 10.1006/abbi.1996.9820 http://doi.org/10.1006/abbi.1996.9820 . A hot spot for hydrogen peroxide-induced damage in the human hypoxia-inducible factor 1 binding site of the PGK 1 gene S Rodriguez-Rodero , JL Fernández-Morera , AF Fernandez , 等 . Epigenetic regulation of aging . Discov Med , 2010 . 10 ( 52 ): 225 - 233 . 20875344 . Epigenetic regulation of aging JY Roignant , M Soller . m 6 A in mRNA: an ancient mechanism for fine-tuning gene expression . Trends Genet , 2017 . 33 ( 6 ): 380 - 390 . 28499622 DOI: 10.1016/j.tig.2017.04.003 http://doi.org/10.1016/j.tig.2017.04.003 . m6A in mRNA: an ancient mechanism for fine-tuning gene expression A Scuteri , S Sanna , WM Chen , 等 . Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits . PLoS Genet , 2007 . 3 ( 7 ): e115 17658951 DOI: 10.1371/journal.pgen.0030115 http://doi.org/10.1371/journal.pgen.0030115 . Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits F Shen , W Huang , JT Huang , 等 . Decreased N 6 -methyladenosine in peripheral blood RNA from diabetic patients is associated with FTO expression rather than ALKBH5 . J Clin Endocrinol Metab , 2015 . 100 ( 1 ): E148 - E154 . 25303482 DOI: 10.1210/jc.2014-1893 http://doi.org/10.1210/jc.2014-1893 . Decreased N6-methyladenosine in peripheral blood RNA from diabetic patients is associated with FTO expression rather than ALKBH5 A Singhal , G Arora , A Sajid , 等 . Regulation of homocysteine metabolism by Mycobacterium tuberculosis S-adenosylhomocysteine hydrolase . Sci Rep, 3:2264 , 2013 . DOI: 10.1038/srep02264 http://doi.org/10.1038/srep02264 . Regulation of homocysteine metabolism by Mycobacterium tuberculosis S-adenosylhomocysteine hydrolase N Smart , CA Risebro , AAD Melville , 等 . Thymosin β-4 is essential for coronary vessel development and promotes neovascularization via adult epicardium . Ann N Y Acad Sci , 2007 . 1112 ( 1 ): 171 - 188 . 17495252 DOI: 10.1196/annals.1415.000 http://doi.org/10.1196/annals.1415.000 . Thymosin β-4 is essential for coronary vessel development and promotes neovascularization via adult epicardium AJP Smith , SE Humphries . Cytokine and cytokine receptor gene polymorphisms and their functionality . Cytokine Growth Factor Rev , 2009 . 20 ( 1 ): 43 - 59 . 19038572 DOI: 10.1016/j.cytogfr.2008.11.006 http://doi.org/10.1016/j.cytogfr.2008.11.006 . Cytokine and cytokine receptor gene polymorphisms and their functionality TG Smith , PA Robbins , PJ Ratcliffe . The human side of hypoxia-inducible factor . Br J Haematol , 2008 . 141 ( 3 ): 325 - 334 . 18410568 DOI: 10.1111/j.1365-2141.2008.07029.x http://doi.org/10.1111/j.1365-2141.2008.07029.x . The human side of hypoxia-inducible factor ZD Smith , MM Chan , TS Mikkelsen , 等 . A unique regulatory phase of DNA methylation in the early mammalian embryo . Nature , 2012 . 484 ( 7394 ): 339 - 344 . 22456710 DOI: 10.1038/nature10960 http://doi.org/10.1038/nature10960 . A unique regulatory phase of DNA methylation in the early mammalian embryo HW Song , X Feng , H Zhang , 等 . METTL3 and ALKBH5 oppositely regulate m 6 A modification of TFEB mRNA, which dictates the fate of hypoxia/reoxygenation-treated cardiomyocytes . Autophagy , 2019 . 15 ( 8 ): 1419 - 1437 . 30870073 DOI: 10.1080/15548627.2019.1586246 http://doi.org/10.1080/15548627.2019.1586246 . METTL3 and ALKBH5 oppositely regulate m6A modification of TFEB mRNA, which dictates the fate of hypoxia/reoxygenation-treated cardiomyocytes JE Souness , JE Stouffer , VC de Sanchez . Effect of N 6 -methyladenosine on fat-cell glucose metabolism: evidence for two modes of action . Biochem Pharmacol , 1982 . 31 ( 24 ): 3961 - 3971 . 6297505 DOI: 10.1016/0006-2952(82)90642-6 http://doi.org/10.1016/0006-2952(82)90642-6 . Effect of N6-methyladenosine on fat-cell glucose metabolism: evidence for two modes of action JR Speakman , KA Rance , AM Johnstone . Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure . Obesity (Silver Spring) , 2008 . 16 ( 8 ): 1961 - 1965 . 18551109 DOI: 10.1038/oby.2008.318 http://doi.org/10.1038/oby.2008.318 . Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure FL Tan , CS Moravec , JB Li , 等 . The gene expression fingerprint of human heart failure . Proc Natl Acad Sci USA , 2002 . 99 ( 17 ): 11387 - 11392 . DOI: 10.1073/pnas.162370099 http://doi.org/10.1073/pnas.162370099 . The gene expression fingerprint of human heart failure NJ Timpson , PM Emmett , TM Frayling , 等 . The fat mass- and obesity-associated locus and dietary intake in children . Am J Clin Nutr , 2008 . 88 ( 4 ): 971 - 978 . 18842783 DOI: 10.1093/ajcn/88.4.971 http://doi.org/10.1093/ajcn/88.4.971 . The fat mass- and obesity-associated locus and dietary intake in children B van Wijk , G van den Berg , R Abu-Issa , 等 . Epicardium and myocardium separate from a common precursor pool by crosstalk between bone morphogenetic protein-and fibroblast growth factor-signaling pathways . Circ Res , 2009 . 105 ( 5 ): 431 - 441 . 19628790 DOI: 10.1161/circresaha.109.203083 http://doi.org/10.1161/circresaha.109.203083 . Epicardium and myocardium separate from a common precursor pool by crosstalk between bone morphogenetic protein-and fibroblast growth factor-signaling pathways CY Wang , SS Shie , MS Wen , 等 . Loss of FTO in adipose tissue decreases Angptl4 translation and alters triglyceride metabolism . Sci Signal , 2015 . 8 ( 407 ): ra127 26671148 DOI: 10.1126/scisignal.aab3357 http://doi.org/10.1126/scisignal.aab3357 . Loss of FTO in adipose tissue decreases Angptl4 translation and alters triglyceride metabolism X Wang , C He . Reading RNA methylation codes through methyl-specific binding proteins . RNA Biol , 2014 . 11 ( 6 ): 669 - 672 . 24823649 DOI: 10.4161/rna.28829 http://doi.org/10.4161/rna.28829 . Reading RNA methylation codes through methyl-specific binding proteins Y Wang , Y Li , JI Toth , 等 . N 6 -methyladenosine modification destabilizes developmental regulators in embryonic stem cells . Nat Cell Biol , 2014 . 16 ( 2 ): 191 - 198 . 24394384 DOI: 10.1038/ncb2902 http://doi.org/10.1038/ncb2902 . N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells C Weber , H Noels . Atherosclerosis: current pathogenesis and therapeutic options . Nat Med , 2011 . 17 ( 11 ): 1410 - 1422 . 22064431 DOI: 10.1038/nm.2538 http://doi.org/10.1038/nm.2538 . Atherosclerosis: current pathogenesis and therapeutic options CM Wei , B Moss . Nucleotide sequences at the N 6 -methyladenosine sites of HeLa cell messenger ribonucleic acid . Biochemistry , 1977 . 16 ( 8 ): 1672 - 1676 . 856255 . Nucleotide sequences at the N6-methyladenosine sites of HeLa cell messenger ribonucleic acid WQ Wei , XY Ji , XQ Guo , 等 . Regulatory role of N 6 -methyladenosine (m 6 A) methylation in RNA processing and human diseases . J Cell Biochem , 2017 . 118 ( 9 ): 2534 - 2543 . 28256005 DOI: 10.1002/jcb.25967 http://doi.org/10.1002/jcb.25967 . Regulatory role of N6-methyladenosine (m6A) methylation in RNA processing and human diseases AK Wilkins , PI Barton , B Tidor . The Per2 negative feedback loop sets the period in the mammalian circadian clock mechanism . PLoS Comput Biol , 2007 . 3 ( 12 ): e242 18085817 DOI: 10.1371/journal.pcbi.0030242 http://doi.org/10.1371/journal.pcbi.0030242 . The Per2 negative feedback loop sets the period in the mammalian circadian clock mechanism EM Winter , ACGD Groot . Epicardium-derived cells in cardiogenesis and cardiac regeneration . Cell Mol Life Sci , 2007 . 64 ( 6 ): 692 - 703 . 17380310 DOI: 10.1007/s00018-007-6522-3 http://doi.org/10.1007/s00018-007-6522-3 . Epicardium-derived cells in cardiogenesis and cardiac regeneration C Wong , P Kanetsky , D Raj . Genetic polymorphisms of the RAS-cytokine pathway and chronic kidney disease . Pediatr Nephrol , 2008 . 23 ( 7 ): 1037 - 1051 . 18481112 DOI: 10.1007/s00467-008-0816-z http://doi.org/10.1007/s00467-008-0816-z . Genetic polymorphisms of the RAS-cytokine pathway and chronic kidney disease Y Xuan , LN Wang , H Zhi , 等 . Association between 3 IL-10 gene polymorphisms and cardiovascular disease risk: systematic review with meta-analysis and trial sequential analysis . Medicine (Baltimore) , 2016 . 95 ( 6 ): e2846 26871859 DOI: 10.1097/md.0000000000002846 http://doi.org/10.1097/md.0000000000002846 . Association between 3 IL-10 gene polymorphisms and cardiovascular disease risk: systematic review with meta-analysis and trial sequential analysis Y Yang , F Shen , W Huang , 等 . Glucose is involved in the dynamic regulation of m 6 A in patients with type 2 diabetes . J Clin Endocrinol Metab , 2019 . 104 ( 3 ): 665 - 673 . 30137347 DOI: 10.1210/jc.2018-00619 http://doi.org/10.1210/jc.2018-00619 . Glucose is involved in the dynamic regulation of m6A in patients with type 2 diabetes SL Zhong , HY Li , Z Bodi , 等 . MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor . Plant Cell , 2008 . 20 ( 5 ): 1278 - 1288 . 18505803 DOI: 10.1105/tpc.108.058883 http://doi.org/10.1105/tpc.108.058883 . MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor B Zhou , Q Ma , S Rajagopal , 等 . Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart . Nature , 2008 . 454 ( 7200 ): 109 - 113 . 18568026 DOI: 10.1038/nature07060 http://doi.org/10.1038/nature07060 . Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart Compliance with ethics guidelines Kun ZHAO, Chuan-xi YANG, Peng LI, Wei SUN, and Xiang-qing KONG declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. 10.1631/jzus.B1900680 Project supported by the Grants-in-Aid from the Graduate Research and Innovation Projects of Jiangsu Province (No. KYCX18_1461), China 2019-12-05 2020-02-28 2022-01-05 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2020 2020 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 07 21