Here we report the identification and verification of a β-hydroxybutyrate-derived protein modification, lysine β-hydroxybutyrylation (Kbhb), as a new type of histone mark. Histone Kbhb marks are dramatically induced in response to elevated β-hydroxybutyrate levels in cultured cells and in livers from mice subjected to prolonged fasting or streptozotocin-induced diabetic ketoacidosis. In total, we identified 44 histone Kbhb sites, a figure comparable to the known number of histone acetylation sites. By ChIP-seq and RNA-seq analysis, we demonstrate that histone Kbhb is a mark enriched in active gene promoters and that the increased H3K9bhb levels that occur during starvation are associated with genes upregulated in starvation-responsive metabolic pathways. Histone β-hydroxybutyrylation thus represents a new epigenetic regulatory mark that couples metabolism to gene expression, offering a new avenue to study chromatin regulation and diverse functions of β-hydroxybutyrate in the context of important human pathophysiological states, including diabetes, epilepsy, and neoplasia. Xie et al. identify a new type of histone modification-lysine β-hydroxybutyrylation. This modification is induced significantly during prolonged fasting in mouse liver and is associated with genes upregulated in starvation-responsive metabolic pathways (amino acid metabolism, redox homeostasis, circadian rhythm, and PPAR signaling).
Bibliographical noteFunding Information:
We are grateful to Saadi Khochibin, Wei Gu, Lev Becker, Mindian Li, and Benjamin R. Sabari for valuable discussion. This work was supported by the following grants and agencies: NIH DK089098, P01 DK057751, CT DPH 2014-0139, and Ellison Medical Foundation to X.Y.; NIH DK71900 and the Starr Foundation Tri-Institutional Stem Cell Initiative (2014-021) to R.G.R.; NIH R01GM101171 and R21CA177925 to D.B.L.; NIH GM59507 to H.Z.; NIH R01AG030593 and R01AG023166 to S.D.P.; National Natural Science Foundation of China (81125023) and Shanghai Commission of Science and Technology (14431902800) to Jingya Li and Jia Li; and National Basic Research Program of China (973 Program) (No. 2014CBA02004) and the Shanghai Municipal Science and Technology Commission (No. 15410723100) to M.T. Y.Z. is supported by the Nancy and Leonard Florsheim Family Fund and is a member of the scientific advisory board and shareholder of PTM BioLabs.