MTCH2 promotes adipogenesis in intramuscular preadipocytes via an m ⁶ A‐YTHDF1‐dependent mechanism

Abstract

Intramuscular fat is considered a potential factor that is associated with meat quality in animal production and insulin resistance in humans. N6‐methyladenosine (m6A) modification of mRNA plays an important role in regulating adipogenesis. However, the effects of m6A on the adipogenesis of intramuscular preadipocytes and associated mechanisms remain unknown. Here, we performed m6A sequencing to compare m6A methylome of the longissimus dorsi muscles (LDMs) between Landrace pigs (lean‐type breed) and Jinhua pigs (obese‐type breed with higher levels of intramuscular fat). Transcriptome‐wide m6A profiling of porcine LDMs was highly conserved with humans and mice. Furthermore, we identified a unique methylated gene in Jinhua pigs named mitochondrial carrier homology 2 (MTCH2). The m6A levels oiMTCHl mRNA were reduced by introducing a synonymous mutation, and adipogenesis test results showed that the MTCH2 mutant was inferior with regard to adipogenesis compared with the MTCH2 wild‐type. We then found that MTCH2 protein expression was positively associated with m6A levels, and an YTH domain family protein 1‐RNA immunoprecipitation‐quantitative PCR assay indicated that MTCH2 mRNA was a target of the YTH domain family protein 1. This study provides comprehensive m6A profiles of LDM transcriptomes in pigs and suggests an essential role for m6A modification of MTCH2 in intramuscular fat regulation.—Jiang, Q., Sun, B., Liu, Q., Cai, M., Wu, R., Wang, F., Yao, Y., Wang, Y., Wang, X. MTCH2 promotes adipogenesis in intramuscular preadipocytes via an m6A‐YTHDF1‐dependent mechanism. FASEB J. 33, 2971–2981 (2019). http://www.fasebj.org

m6A-binding proteins: the emerging crucial performers in epigenetics

“…In addition to YTHDF2, m 6 A-binding protein YTHDF1 also participates in the process of adipogenesis. Jiang et al determined the whole transcriptome-wide m 6 A profiles of the longissimus dorsi muscles (LDMs) in lean-type and obese-type pigs and found a unique m 6 Amethylated gene in the obese-type pigs called MTCH2 that was involved in lipid accumulation and oxidation [114]. And YTHDF1 targeted at the m 6 A motif of MTCH2 mRNA to improve its translation efficiency and further promote adipogenesis.…”

N6-methyladenosine modification modulate in the heat stress of sheep (Ovis aries)

“…As a chemical marker, m 6 A has been identified in many animal and plant genes, and exerts effects in important biological pathways [49,50]. Zhou et al showed that HSP70 mRNA containing m 6 A modification sites in the 5 UTR underwent independent translation without depending on the N 7methylguanosine cap, while methylation was increased in the 5 UTR after HSP70 heat shock [20].…”

Function and evolution of RNA N6-methyladenosine modification

“…ZFP217 directly activates the FTO transcription by binding to its promoter and interacts with YTHDF2 to maintain FTO-induced m 6 A demethylation, thereby facilitating adipogenesis of 3T3-L1 cells [66]. m 6 A methylation expedites adipogenesis of intramuscular preadipocyte through enhancing MTCH2 expression in a YTHDF1-dependent mRNA translation [69]. Besides, m 6 A participates in heat stress-associated lipid metabolism, and its regulators including METTL14, WTAP, FTO, and YTHDF2 and m 6 A levels are increased in the liver and abdominal fat of neonatal piglets following heat stress exposure [70].…”