Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation.
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.
Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
Zhongyu
Z
Xie
Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
Di
D
Zhang
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.
Dongjun
D
Chung
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
Zhanyun
Z
Tang
Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
He
H
Huang
Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
Lunzhi
L
Dai
Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
Shankang
S
Qi
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Jingya
J
Li
Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
Gozde
G
Colak
Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
Yue
Y
Chen
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Chunmei
C
Xia
Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
Chao
C
Peng
Section of Comparative Medicine and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Haibin
H
Ruan
Institute for Genomics and Systems Biology, The University of Chicago, Chicago, IL 60637, USA.
Matt
M
Kirkey
Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
Danli
D
Wang
Department of Molecular and Integrative Physiology and Geriatrics Center, University of Michigan, Ann Arbor, MI 48109, USA.
Lindy M
LM
Jensen
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.
Oh Kwang
OK
Kwon
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.
Sangkyu
S
Lee
Department of Molecular and Integrative Physiology and Geriatrics Center, University of Michigan, Ann Arbor, MI 48109, USA.
Scott D
SD
Pletcher
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Minjia
M
Tan
Department of Pathology and Institute of Gerontology, University of Michigan, Ann Arbor, MI 48109, USA.
David B
DB
Lombard
Institute for Genomics and Systems Biology, The University of Chicago, Chicago, IL 60637, USA.
Kevin P
KP
White
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.
Hongyu
H
Zhao
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Jia
J
Li
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
Robert G
RG
Roeder
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.
Xiaoyong
X
Yang
Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA. Electronic address: yingming.zhao@uchicago.edu.
Yingming
Y
Zhao
D000818:Animals; D001665:Binding Sites; D042002:Chromatin Assembly and Disassembly; D016883:Diabetic Ketoacidosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004734:Energy Metabolism; D044127:Epigenesis, Genetic; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006885:Hydroxybutyrates / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008239:Lysine; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D013217:Starvation / Q000235:genetics / Q000378:metabolism*; D013311:Streptozocin
D005227:Fatty Acids; D006657:Histones; D006885:Hydroxybutyrates; D013311:Streptozocin; D005947:Glucose; D008239:Lysine