Histone lysine methacrylation is a dynamic post-translational modification regulated by HAT1 and SIRT2
Kyle Delaney, Minjia Tan, Zhesi Zhu, Jinjun Gao, Lunzhi Dai, Sun‐Joo Kim, Jun Ding, Maomao He, Levon Halabelian, Lu Yang, Prabakaran Nagarajan, Mark R. Parthun, Sangkyu Lee, Saadi Khochbin, Y. George Zheng, Yingming Zhao
Abstract
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.