Emerging role of m⁶A RNA methylation in nutritional physiology and metabolism

Abstract

N 6 -methyladenine (m 6 A) is the most prevalent type of internal RNA methylation in eukaryotic mRNA and plays critical roles in regulating gene expression for fundamental cellular processes and diverse physiological functions. Recent evidence indicates that m 6 A methylation regulates physiology and metabolism, and m 6 A has been increasingly implicated in a variety of human diseases, including obesity, diabetes, metabolic syndrome and cancer. Conversely, nutrition and diet can modulate or reverse m 6 A methylation patterns on gene expression. In this review, we summarize the recent progress in the study of the m 6 A methylation mechanisms and highlight the crosstalk between m 6 A modification, nutritional physiology and metabolism. KEYWORDS epitranscriptomic, M 6 A RNA methylation, metabolism, nutrition 1 | INTRODUCTION More than 100 types of chemical modifications have been discovered in cellular RNAs. 1 Reversible RNA modifications are an emerging layer of posttranscriptional gene regulation, 2,3 which exerts a large number of physiological processes and biological functions. 4,5 As a novel epitranscriptomic marker, the dynamic and reversible chemical N 6methyladenine (m 6 A) modification is the most abundant internal modification in mRNA. In mammals, plants and some prokaryotes, m 6 A is widely involved in mRNA metabolism, including mRNA stability, 6 mRNA splicing, 7,8 RNA nucleation, 9 RNA-protein interactions 10 and mRNA translation. 11The m 6 A modification plays an important role in nutritional physiology and metabolism, such as controlling circadian rhythms, 12,13 lipid accumulation 14 and adipogenesis. 15,16 The dysregulation of m 6 A patterns causes abnormal gene expression and functions, aberrant cell differentiation and cellular homeostasis imbalance, leading to the occurrence of certain inflammatory states, metabolic diseases and cancer. 9,17,18 Therefore, the effects of m 6 A RNA methylation on physiology and metabolism have become a research hotspot in the RNA Abbreviations: m 6 A, N 6 -methyladenine; 3'-UTRs, 3'untranslated regions; CDS, coding sequence; MTC, methyltransferase cpmplex; METTL3, methyltransferase-like 3; METTL14, methyltransferase-like 14; WTAP, Wilms' tumour 1-associating protein; ZC3H13, zinc finger CCCH-type containing 13; RBM15/15B, RNA binding motif protein 15/15B; FTO, fat mass and obesity-associated protein; ALKBH5, AlkB homolog 5; YTHDF1/2/3, YTH domain family 1/2/3; YTHDC1/2, YTH domain containing 1/2; SAM, S-adenosylmethionine; hm 6 A, N 6hydroxymethyladenosine; f 6 A, N 6 -formyladenosine; A, adenosine; m 6 A m , N 6 ,2'-O-dimethyladenosine; DCP2, decapping mRNA 2; snRNA, small nuclear RNA; eIF3, eukaryotic initiation factor 3; SRSF3, serine/arginine-rich splicing factor 3; SRSF10, serine/arginine-rich splicing factor 10; HNRNPA2B1, heterogenous nuclear ribonucleoprotein A2B1; HNRNPC, heterogenous nuclear ribonucleoprotein C; DGCR8, DiGeorge syndrome critical region gene 8; IGF2BP1/2/3, insulin-like growth factor 2 mRNA-binding protein 1/2/3; T2DM, type 2 diabetes melli...

Resveratrol Attenuates Aflatoxin B1-Induced ROS Formation and Increase of m6A RNA Methylation

“…Emerging evidence indicates that the dynamic and reversible nature of m 6 A modification plays a critical role in nutritional physiology and metabolism [20]. In this study, we found that AFB 1 significantly increased the protein expression of METTL3, whereas it markedly reduced the expression of FTO in the liver, and increased the level of m 6 A.…”

“…It is worth noting that the network of DNA methylation and histone modification, in part, regulates AFB 1 -induced liver injury [7], whereas few investigations have uncovered the crosstalk between RNA methylation and AFB 1 -induced liver damage. M 6 A is the most common prevalent internal RNA methylation modification that exerts its biological functions, including the regulation of mRNA splicing, export, localization, stability, and translation [20,31], and regulates gene expression.…”

“…These results highlight the effective protection of resveratrol in AFB 1 -induced liver injury. Fascinatingly, emerging observations indicated that nutritional challenges, such as a high-fat diet, a dietary fasting state, and dietary supplement with betaine, cycloleucine, and curcumin [20,46] regulate the gene expression by m 6 A RNA methylation. Here, we also found that dietary resveratrol supplementation in AFB 1 -treated mice significantly reduced the level of m 6 A compared with the AFB 1 group.…”

“…The dysregulation of m 6 A patterns contributes to abnormal circadian rhythms, defective physiological functions, and aberrant nutritional metabolism, highlighting its role in obesity, hepatic diseases, and cancer [17][18][19]. Interestingly, emerging observations suggested that the m 6 A modification responds and adapts quickly to nutritional challenges, such as a high-fat diet or fasting, and supplementation of betaine, cycloleucine, and curcumin [20]. Thus, it is an interesting hotspot to explore the mechanism of how precisely m 6 A RNA methylation affects AFB 1 -induced liver damage.…”

The Effects of METTL3-Mediated Regulations of the Adipogenic Differentiations of Bone Marrow MSCs Targeting PI3K/AKT Pathways on the Chemo-Resistance of AML

“…The epigenetic regulation of mRNA is an important factor affecting stem cell differentiation [10] . N 6methyladenine (m 6 A) is the most abundant, dynamic, and reversible RNA modification for eukaryotic mRNA [11,12] . The m 6 A is carried out with the participation of methyltransferase complexes (writers, such as METTL3, METTL14, and WTAP); demethylase (erasers, such as ALKBH5 and FTO); and m 6 A reader proteins (readers, such as YTH family and IGF2BP family), which have the ability to dynamically and reversibly regulate RNA splicing, transport, translation, and stability [13][14][15] .…”