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  2. Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation

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.
Zhongyu Xie 1 Di Zhang 1 Dongjun Chung 2 Zhanyun Tang 3 He Huang 1 Lunzhi Dai 1 Shankang Qi 1 Jingya Li 4 Gozde Colak 1 Yue Chen 1 Chunmei Xia 4 Chao Peng 1 Haibin Ruan 5 Matt Kirkey 6 Danli Wang 1 Lindy M Jensen 7 Oh Kwang Kwon 8 Sangkyu Lee 8 Scott D Pletcher 7 Minjia Tan 4 David B Lombard 9 Kevin P White 6 Hongyu Zhao 10 Jia Li 4 Robert G Roeder 3 Xiaoyong Yang 11 Yingming Zhao 12
Affiliations

Affiliations

  • 1 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
  • 2 Department of Biostatistics, Yale School of Public Health, New Haven, CT 06520, USA; Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
  • 3 Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 Section of Comparative Medicine and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 6 Institute for Genomics and Systems Biology, The University of Chicago, Chicago, IL 60637, USA.
  • 7 Department of Molecular and Integrative Physiology and Geriatrics Center, University of Michigan, Ann Arbor, MI 48109, USA.
  • 8 BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
  • 9 Department of Pathology and Institute of Gerontology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 10 Department of Biostatistics, Yale School of Public Health, New Haven, CT 06520, USA; Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06511, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA.
  • 11 Section of Comparative Medicine and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: xiaoyong.yang@yale.edu.
  • 12 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA. Electronic address: yingming.zhao@uchicago.edu.
Abstract

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.

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