ACSS2 coupled with KAT7 regulates histone β-hydroxybutyrylation to enhance transcription
Siyu Wang, Ziping Niu, Yingao Zhang, Ruilong Liu, Rui Zhu, Yuxuan Sun, Yanpu Han, Aiyuan Wang, Jianji Zhang, Hui Zhang, Yong Zang, Yingming Zhao, Guijin Zhai, Kai Zhang
Abstract
Histone lysine β-hydroxybutyrylation (Kbhb) is an epigenetic mark linking ketone metabolism to transcription. However, the molecular mechanism by which β-hydroxybutyrate is converted to β-hydroxybutyryl-coenzyme A (BHB-CoA), the cofactor for Kbhb, remains unknown. Here, we report that acetyl-CoA synthetase short-chain family member 2 (ACSS2) coupled with lysine acetyltransferase 7 (KAT7) modulates β-hydroxybutyrylation on lysine 9 of histone H3 (H3K9bhb) to promote transcription. We show that KAT7 serves as a β-hydroxybutyryltransferase and preferably catalyzes histone Kbhb, especially H3K9bhb, in 1171 identified Kbhb substrates. ACSS2 is a BHB-CoA synthetase. This enzyme can sense cellular β-hydroxybutyrate and translocate into the nucleus, where it binds to and colocalizes with KAT7 at specific locus of chromatin. The ACSS2-generated BHB-CoA can fuel KAT7 for histone H3K9bhb. We demonstrate that the β-hydroxybutyrate drives the ACSS2-KAT7-H3K9bhb axis to promote epigenetic regulation and tumor cell growth. Our study not only identifies the founding member of BHB-CoA ligase but also reveals the mechanism underlying KAT7-catalyzed histone Kbhb using ACSS2-generated BHB-CoA.