Metabolic Regulation of Gene Expression by Histone Lysine β‐hydroxybutyrylation

®‐hydroxybutyrate has been used to treat epilepsy and plays a neuro‐protective role in models of neurodegenerative diseases. Ketogenic diets are under evaluation as adjunctive treatment for patients with brain tumors and other malignancies. These lines of evidence suggest a regulatory role for ketone bodies beyond serving as an energy source. However, the mechanisms underlying these physiological and pharmacological effects of ketone bodies remain largely unknown. We had previously identified lysine ®‐hydroxybutyrylation (Kbhb) as a new type of histone modification. We showed that histone Kbhb is dramatically induced in livers from mice subjected to prolonged fasting or streptozotocin‐induced diabetic ketoacidosis. By ChIP‐seq and RNA‐seq analysis, we demonstrated that histone Kbhb is a mark enriched in active gene promoters, and that the increased H3K9bhb levels during starvation are associated with genes up‐regulated in starvation‐responsive metabolic pathways. We now have new data to show that p300 can catalyze histone Kbhb both in vitro and in cultured cell lines. Using in vitro transcription assay with recombinant chromatin, we demonstrate that p300‐catalyzed histone Kbhb can activate transcription directly. All together, our study suggest histone Kbhb as a new epigenetic regulatory mark that couples metabolism to gene expression, offering a new avenue to study chromatin regulation and the diverse functions of ®‐hydroxybutyrate in the context of important human pathophysiological states, including diabetes, epilepsy, and neoplasia. Support or Funding Information The work was supported by: 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.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 J.L and J.L.; National Basic Research Program of China (973 Program) (No. 2014CBA02004) and the Shanghai Municipal Science and Technology Commission (No. 15410723100) to M.T.