4.7 Article

Histone lysine methacrylation is a dynamic post-translational modification regulated by HAT1 and SIRT2

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CELL DISCOVERY
卷 7, 期 1, 页码 -

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SPRINGERNATURE
DOI: 10.1038/s41421-021-00344-4

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资金

  1. University of Chicago
  2. NIH [R01GM135504, R01DK118266, R01GM062970, RO1AR078555]
  3. Fondation ARC [PGA1RF2019208471]
  4. ANR Episperm4 program
  5. NSF [1808087]
  6. Nancy and Leonard Florsheim family fund
  7. Plan Cancer [CH7INS15B66, C7H-KIC19N30-IAB, ASC16012CSA]
  8. INCa-IReSP [R19051CC]
  9. University Grenoble Alpes [ANR-15-IDEX-02]
  10. AbbVie
  11. Bayer Pharma AG
  12. Boehringer Ingelheim
  13. Canada Foundation for Innovation
  14. Eshelman Institute for Innovation
  15. Genentech
  16. Genome Canada through Ontario Genomics Institute [OGI-196]
  17. EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN grant] [875510]
  18. Janssen
  19. Novartis Pharma AG
  20. Pfizer
  21. Sao Paulo Research Foundation-FAPESP
  22. Takeda
  23. Wellcome Trust
  24. Merck Co.
  25. Division Of Chemistry
  26. Direct For Mathematical & Physical Scien [1808087] Funding Source: National Science Foundation

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Histone lysine methacrylation (Kmea) is a newly discovered type of histone posttranslational modification, confirmed through diverse chemical approaches and identification of 27 modified histone sites. The modification is shown to be a dynamic mark controlled by HAT1 as a methacryltransferase and SIRT2 as a de-methacrylase, suggesting its involvement in epigenome-associated metabolic pathways.
Histone lysine crotonylation is a posttranslational modification with demonstrated functions in transcriptional regulation. Here we report the discovery of a new type of histone posttranslational modification, lysine methacrylation (Kmea), corresponding to a structural isomer of crotonyllysine. We validate the identity of this modification using diverse chemical approaches and further confirm the occurrence of this type of histone mark by pan specific and site-specific anti-methacryllysine antibodies. In total, we identify 27 Kmea modified histone sites in HeLa cells using affinity enrichment with a pan Kmea antibody and mass spectrometry. Subsequent biochemical studies show that histone Kmea is a dynamic mark, which is controlled by HAT1 as a methacryltransferase and SIRT2 as a de-methacrylase. Altogether, these investigations uncover a new type of enzyme-catalyzed histone modification and suggest that methacrylyl-CoA generating metabolism is part of a growing number of epigenome-associated metabolic pathways.

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