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.
Chen Wang  1 ,  Hideki Tanizawa  2  3 ,  Connor Hill  4 ,  Aaron Havas  5 ,  Qiang Zhang  4 ,  Liping Liao  1 ,  Xue Hao  1 ,  Xue Lei  5 ,  Lu Wang  6 ,  Hao Nie  1 ,  Yuan Qi  7 ,  Bin Tian  4 ,  Alessandro Gardini  4 ,  Andrew V Kossenkov  8 ,  Aaron Goldman  9 ,  Shelley L Berger  6 ,  Ken-Ichi Noma  2  3 ,  Peter D Adams  5 ,  Rugang Zhang  10
Affiliations
  • 1. Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
  • 2. Institute of Molecular Biology, University of Oregon, Eugene, OR, 97403, USA.
  • 3. Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan.
  • 4. Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, 19104, USA.
  • 5. Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA, USA.
  • 6. Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 7. Department of Bioinformatics & Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
  • 8. Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.
  • 9. Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.
  • 10. Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA. [email protected].
PMID: 38926365 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.

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