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

• Published in: Cell discovery Vol. 7; no. 1; p. 122
• Main Authors: Delaney, Kyle, Tan, Minjia, Zhu, Zhesi, Gao, Jinjun, Dai, Lunzhi, Kim, Sunjoo, Ding, Jun, He, Maomao, Halabelian, Levon, Yang, Lu, Nagarajan, Prabakaran, Parthun, Mark Robert, Lee, Sangkyu, Khochbin, Saadi, Zheng, Yujun George, Zhao, Yingming
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 28.12.2021; Springer Nature B.V; Nature; Nature Publishing Group
• Subjects: 631/337/475; 631/80/458; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Cycle Analysis; Cell Physiology; Enzymes; Gene regulation; Histones; Life Sciences; Lysine; Mass spectroscopy; Metabolic pathways; Metabolism; Metabolites; Peptides; Post-translation; Proteins; Stem Cells; Transcription
• ISSN: 2056-5968; 2056-5968
• DOI: 10.1038/s41421-021-00344-4

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.