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Abstract：
Although 5-methylcytosine (m5C) has been identified as a novel and abundant mRNA modification and associated with energy metabolism, its regulation function in adipose tissue and skeletal muscle is still limited. This study aimed at investigating the effect of mRNA m5C on adipogenesis and myogenesis using Jinhua pigs (J), Yorkshire pigs (Y) and their hybrids Yorkshire-Jinhua pigs (YJ). We found that Y grow faster than J and YJ, while fatness-related characteristics observed in Y were lower than those of J and YJ. Besides, total mRNA m5C levels and expression rates of NSUN2 were higher both in backfat layer (BL) and longissimus dorsi muscle (LDM) of Y compared to J and YJ, suggesting that higher mRNA m5C levels positively correlate with lower fat and higher muscle mass. RNA bisulfite sequencing profiling of m5C revealed tissue-specific and dynamic features in pigs. Functionally, hyper-methylated m5C-containing genes were enriched in pathways linked to impaired adipogenesis and enhanced myogenesis. In in vitro, m5C inhibited lipid accumulation and promoted myogenic differentiation. Furthermore, YBX2 and SMO were identified as m5C targets. Mechanistically, YBX2 and SMO mRNAs with m5C modification were recognized and exported into the cytoplasm from the nucleus by ALYREF, thus leading to increased YBX2 and SMO protein expression and thereby inhibiting adipogenesis and promoting myogenesis, respectively. Our work uncovered the critical role of mRNA m5C in regulating adipogenesis and myogenesis via ALYREF-m5C-YBX2 and ALYREF-m5C-SMO manners, providing a potential therapeutic target in the prevention and treatment of obesity, skeletal muscle dysfunction and metabolic disorder diseases.
摘要：
尽管5-甲基胞嘧啶（m5C）已被确定为一种新颖且丰富的mRNA修饰，并且与能量代谢有关，其在脂肪组织和骨骼肌中的调节功能仍然有限。本研究旨在研究m5CmRNA对金华猪脂肪生成和肌生成的影响（J），约克郡猪（Y）及其杂种约克郡-金华猪（YJ）。我们发现Y的生长速度比J和YJ快,而在Y中观察到的脂肪相关特征低于J和YJ。此外,与Y和YJ相比，Y的背脂层（BL）和背最长肌（LDM）中m5C的总mRNA水平和NSUN2的表达率均较高，表明较高的m5CmRNA水平与较低的脂肪和较高的肌肉质量呈正相关。m5C的RNA亚硫酸氢盐测序分析揭示了猪的组织特异性和动态特征。功能上,含m5C的高甲基化基因在与脂肪生成受损和肌生成增强相关的途径中富集。在体外，m5C抑制脂质积累并促进肌源性分化。此外，YBX2和SMO被鉴定为m5C靶标。机械上,通过ALYREF识别具有m5C修饰的YBX2和SMOmRNA并将其从细胞核输出到细胞质中，从而导致YBX2和SMO蛋白表达增加，从而抑制脂肪生成和促进肌生成，分别。我们的工作揭示了m5CmRNA在通过ALYREF-m5C-YBX2和ALYREF-m5C-SMO方式调节脂肪生成和肌生成中的关键作用，为肥胖的预防和治疗提供潜在的治疗靶点，骨骼肌功能障碍和代谢紊乱疾病。
