2. Academic Validation
  3. METTL3-mediated chromatin contacts promote stress granule phase separation through metabolic reprogramming during senescence

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

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. rzhang11@mdanderson.org.
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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