METTL3-Mediated Chromatin Contacts Promote Stress Granule Phase Separation Through Metabolic Reprogramming During Senescence

Authors

Chen Wang
Hideki Tanizawa
Connor Hill
Aaron Havas
Qiang Zhang
Liping Liao
Xue Hao
Xue Lei
Lu Wang
Hao Nie
Yuan Qi
Bin Tian
Alessandro Gardini
Andrew V Kossenkov
Aaron Goldman
Shelley L Berger
Ken-Ichi Noma
Peter D Adams
Rugang Zhang

Publication Date

6-26-2024

Journal

Nature Communications

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.

Keywords

Methyltransferases, Chromatin, Cellular Senescence, Humans, Stress Granules, Hexokinase, RNA, Messenger, Adenosine, HEK293 Cells, Metabolic Reprogramming, Phase Separation

DOI

10.1038/s41467-024-49745-5

PMID

38926365

PMCID

PMC11208586

PubMedCentral® Posted Date

6-26-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes