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Mol Cell ; 62(2): 194-206, 2016 04 21.
Article in English | MEDLINE | ID: mdl-27105115

ABSTRACT

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


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