METTL3-mediated chromatin contacts promote stress granule phase separation through metabolic reprogramming during senescence

Nat Commun. 2024 Jun 26;15(1):5410. doi: 10.1038/s41467-024-49745-5.

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.

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / metabolism
  • Cellular Senescence*
  • Chromatin* / metabolism
  • HEK293 Cells
  • Hexokinase / genetics
  • Hexokinase / metabolism
  • Humans
  • Metabolic Reprogramming
  • Methyltransferases* / genetics
  • Methyltransferases* / metabolism
  • Phase Separation
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Stress Granules* / genetics
  • Stress Granules* / metabolism

Substances

  • Methyltransferases
  • Chromatin
  • METTL3 protein, human
  • Hexokinase
  • RNA, Messenger
  • Adenosine