Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation
Open accessAbstract
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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Several uncommon histone modifications, such as histone crotonylation, histone phosphorylation, and histone β-hydroxybutyrylation, are involved in the pathophysiology of MDD.
“Several uncommon histone modifications, such as histone crotonylation, histone phosphorylation, and histone β-hydroxybutyrylation, are shown to be involved in the pathophysiology of MDD.176–178”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [177]
The Discussion (page unavailable) describes histone β-hydroxybutyrylation as a modification that may regulate gene expression, and the Results link it to starvation-responsive metabolic pathways. The paper does not show that it, crotonylation, or phosphorylation is involved in MDD pathophysiology (searched: MDD, depression, and the named modifications). (LLM, conf=0.80)
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- Authors
- Xie, Z., Zhang, D., Chung, D., Tang, Z., Huang, H., Dai, L., Qi, S., Li, J., Colak, G., Chen, Y., Xia, C., Peng, C., Ruan, H., Kirkey, M., Wang, D., Jensen, L. M., Kwon, O. K., Lee, S., Pletcher, S. D., Tan, M., Lombard, D. B., White, K. P., Zhao, H., Li, J., Roeder, R. G., Yang, X., & Zhao, Y.
- Affiliations
- University of Chicago (US)
- Medical University of South Carolina (US)
- Rockefeller University (US)
- Chinese Academy of Sciences (CN)
- University of Michigan (US)
- Kyungpook National University (KR)
- Yale University (US)
- Corresponding author
- Yang, Xiaoyong
- Zhao, Yingming
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 62
- Issue
- 2
- Pages
- 194-206
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC5540445
- OpenAlex
- W2337350186
- Cited by
- 744
- References
- 10
- Citations by year
- 2026: 135 · 2025: 124 · 2024: 91 · 2023: 72 · 2022: 87 · 2021: 79 · 2020: 43 · 2019: 34 · 2018: 37 · 2017: 30 · 2016: 10 · 2015: 1
- FWCI
- 19.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 385 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (CT DPH 2014-0139, DK089098, P01 DK057751)
- Ellison Medical Foundation (DK71900)
- National Natural Science Foundation of China (81125023)
- Science and Technology Commission of Shanghai Municipality (14431902800, 15410723100)
- National Basic Research Program of China (2014CBA02004)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- beta-hydroxybutyrate, histone modifications, epigenetic regulation, metabolic regulation of gene expression, starvation, fasting, diabetic ketoacidosis, chromatin regulation, promoter enrichment, metabolic reprogramming
- MeSH terms
- Animals, Binding Sites, Disease Models, Animal, Energy Metabolism, Fatty Acids, Gene Expression Regulation, Glucose, Histones, Humans, Hydroxybutyrates, Liver, Lysine, Mice, Inbred C57BL, Promoter Regions, Genetic, Protein Processing, Post-Translational, Starvation, Streptozocin, Diabetic Ketoacidosis, Chromatin Assembly and Disassembly, Epigenesis, Genetic, HEK293 Cells
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