The critical roles of m6A modification in metabolic abnormality and cardiovascular diseases

Abstract

N6-methyladenosine (m6A) RNA methylation is an emerging area of epigenetics, which is a reversible and dynamic modification mediating by 'writers' (methylase, adding methyl groups, METTL3, METTL14, and WTAP), 'erasers' (demethylase, deleting methyl groups, FTO and ALKBH5), and 'readers' (YTHDF1-3, YTHDC1 and YTHDC2). Recent studies in human, animal models and cell levels have disclosed a critical role of m6A modification in regulating the homeostasis of metabolic processes and cardiovascular function. Evidence from these studies identify m6A as a candidate of biomarker and therapeutic target for metabolic abnormality and cardiovascular diseases (CVD). Comprehensive understanding of the complexity of m6A regulation in metabolic diseases and CVD will be helpful for us to understand the pathogenesis of CVD. In this review, we discuss the regulatory role of m6A in metabolic abnormality and CVD. We will emphasize the clinical relevance of m6A dysregulation in CVD.

Keywords: Cardiovascular disease; FTO; Heart failure; METTL3; Metabolic syndrome; Myocardial infarction; N6-methyladenosine; RNA epigenetics.

Figure 1

Regulation of gene expression by RNA modifications. (A) Chemical modification of eukaryotic mRNA. (B & C) Mechanism of m6A modification. Installation of methyl groups in m6A modification is accomplished by writers: METTL3, METTL14, WTAP, KIAA1429, METTL16 and RBM15. And the reversal of m6A methylation is mediated by erasers: FTO and ALKBH5. The altered m6A transcripts are recognized by m6A readers, and then leading to different effects on methylated mRNAs.

Figure 2

Regulation of metabolic disorders by m6A. The components of m6A methylation includes writers, erasers, and readers, and they regulate the development of diabetes, obesity and NAFLD by various down-stream targets. The dashed lines mean the nodes are non-intersect. m6A, N6-methyladenosine; METTL3, methyltransferase-like 3; METTL14, methyltransferase-like 14; FTO, fat mass and obesity associated protein; YTHDF1, YTH domain family protein 1; YTHDF2, YTH domain family protein 2; FASN, fatty acid synthase; CCND1, cyclin D1; Akt, also known as protein kinase B; FOXO1, forkhead box protein O1; RUNX1T1, runt-related transcription factor 1; MTCH2, mitochondrial carrier homology 2; CCNA2, cyclin A2; NAFLD, nonalcoholic fatty liver disease.

Figure 3

Regulation of cardiovascular diseases (CVD) by m6A. As a novel regulator of CVD, m6A plays various roles in the development of hypertension, vascular diseases, MI and I/R injury, and heart failure, via different pathways. The dashed lines mean the nodes are non-intersect. m6A, N6-methyladenosine; METTL3, methyltransferase-like 3; METTL14, methyltransferase-like 14; WTAP, Wilms' tumor 1-associating protein; FTO, fat mass and obesity associated protein; ALKBH5, Alk B homologue 5; YTHDF2, YTH domain family protein 2; STAT1, signal transducer and activator of transcription 1; MAPKs, mitogen-activated protein kinases; SERCA2a, sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase 2a; TFEB, transcription factor EB; TWIST1, twist-related protein 1; MI, myocardial infarction; I/R, ischemia/reperfusion.