Metabolic Regulation of Gene Expression by Histone Lysine ?-Hydroxybutyrylation.

ABSTRACT: Here we report the identification and verification of a ?-hydroxybutyrate-derived protein modification, lysine ?-hydroxybutyrylation (Kbhb), as a new type of histone mark. Histone Kbhb marks are dramatically induced in response to elevated ?-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 ?-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 ?-hydroxybutyrate in the context of important human pathophysiological states, including diabetes, epilepsy, and neoplasia.

SUBMITTER: Xie Z 

PROVIDER: S-EPMC5540445 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature