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

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 and Rugang Zhang ()
Additional contact information
Chen Wang: University of Texas M.D. Anderson Cancer Center
Hideki Tanizawa: University of Oregon
Connor Hill: The Wistar Institute
Aaron Havas: Sanford Burnham Prebys Medical Discovery Institute
Qiang Zhang: The Wistar Institute
Liping Liao: University of Texas M.D. Anderson Cancer Center
Xue Hao: University of Texas M.D. Anderson Cancer Center
Xue Lei: Sanford Burnham Prebys Medical Discovery Institute
Lu Wang: University of Pennsylvania
Hao Nie: University of Texas M.D. Anderson Cancer Center
Yuan Qi: University of Texas MD Anderson Cancer Center
Bin Tian: The Wistar Institute
Alessandro Gardini: The Wistar Institute
Andrew V. Kossenkov: The Wistar Institute
Aaron Goldman: The Wistar Institute
Shelley L. Berger: University of Pennsylvania
Ken-ichi Noma: University of Oregon
Peter D. Adams: Sanford Burnham Prebys Medical Discovery Institute
Rugang Zhang: University of Texas M.D. Anderson Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49745-5

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