Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation PMID: 27105115

ADC Targets in Oncology

2026-04-10

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

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: [email protected].
12. Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA. Electronic address: [email protected].

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.