Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation

Mol Cell. 2016 Apr 21;62(2):194-206. doi: 10.1016/j.molcel.2016.03.036.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Chromatin Assembly and Disassembly
  • Diabetic Ketoacidosis / chemically induced
  • Diabetic Ketoacidosis / genetics
  • Diabetic Ketoacidosis / metabolism*
  • Disease Models, Animal
  • Energy Metabolism*
  • Epigenesis, Genetic
  • Fatty Acids / metabolism
  • Gene Expression Regulation*
  • Glucose / metabolism
  • HEK293 Cells
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Hydroxybutyrates / metabolism*
  • Liver / metabolism*
  • Lysine
  • Mice, Inbred C57BL
  • Promoter Regions, Genetic
  • Protein Processing, Post-Translational*
  • Starvation / genetics
  • Starvation / metabolism*
  • Streptozocin


  • Fatty Acids
  • Histones
  • Hydroxybutyrates
  • Streptozocin
  • Glucose
  • Lysine