PDF(Pubmed)
Abstract：
METTL3 is the catalytic subunit of the methyltransferase complex, which mediates m6A modification to regulate gene expression. In addition, METTL3 regulates transcription in an enzymatic activity-independent manner by driving changes in high-order chromatin structure. However, how these functions of the methyltransferase complex are coordinated remains unknown. Here we show that the methyltransferase complex coordinates its enzymatic activity-dependent and independent functions to regulate cellular senescence, a state of stable cell growth arrest. Specifically, METTL3-mediated chromatin loops induce Hexokinase 2 expression through the three-dimensional chromatin organization during senescence. Elevated Hexokinase 2 expression subsequently promotes liquid-liquid phase separation, manifesting as stress granule phase separation, by driving metabolic reprogramming. This correlates with an impairment of translation of cell-cycle related mRNAs harboring polymethylated m6A sites. In summary, our results report a coordination of m6A-dependent and -independent function of the methyltransferase complex in regulating senescence through phase separation driven by metabolic reprogramming.
摘要：
METTL3是甲基转移酶复合物的催化亚基，介导m6A修饰以调节基因表达。此外,METTL3通过驱动高阶染色质结构的变化以不依赖酶活性的方式调节转录。然而,甲基转移酶复合物的这些功能是如何协调的仍然是未知的。在这里，我们表明甲基转移酶复合物协调其酶活性依赖性和独立的功能来调节细胞衰老，稳定的细胞生长停滞状态。具体来说,METTL3介导的染色质环在衰老过程中通过三维染色质组织诱导己糖激酶2表达。Hexopkinase2表达升高随后促进液-液相分离，表现为应力颗粒相分离，通过驱动代谢重编程。这与携带多甲基化m6A位点的细胞周期相关mRNA的翻译受损相关。总之,我们的研究结果报道了甲基转移酶复合物的m6A依赖性和非依赖性功能通过代谢重编程驱动的相分离来调节衰老。
