Review Article | Published:

Integrative regulation of physiology by histone deacetylase 3

Abstract

Cell-type-specific gene expression is physiologically modulated by the binding of transcription factors to genomic enhancer sequences, to which chromatin modifiers such as histone deacetylases (HDACs) are recruited. Drugs that inhibit HDACs are in clinical use but lack specificity. HDAC3 is a stoichiometric component of nuclear receptor co-repressor complexes whose enzymatic activity depends on this interaction. HDAC3 is required for many aspects of mammalian development and physiology, for example, for controlling metabolism and circadian rhythms. In this Review, we discuss the mechanisms by which HDAC3 regulates cell type-specific enhancers, the structure of HDAC3 and its function as part of nuclear receptor co-repressors, its enzymatic activity and its post-translational modifications. We then discuss the plethora of tissue-specific physiological functions of HDAC3.

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Acknowledgements

The authors thank members of the Lazar laboratory for discussion and comments on the manuscript. They also thank H.-W. Lim for processing ChIP-seq and GRO-seq data from GEO data sets (GSE83928 and GSE110056), H. B. Nguyen for bioinformatics analysis of gene expression (GSE98650, GSE90531, GSE83927, GSE72917, GSE50188, GSE85929, GSE33609, GSE79696 and GSE68991) and H. J. Richter for assistance with modelling the crystal structure of HDAC3. US National Institutes of Health (NIH) grant R01 DK45586 (M.A.L.) and NIH F30 DK104513 (M.J.E.) supported this work.

Reviewer information

Nature Reviews Molecular Cell Biology thanks C. Trivedi and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

M.J.E. and M.A.L. researched data for the article, made substantial contributions to the writing and content and reviewed and edited the manuscript before submission.

Competing interests

M.A.L. is a consultant to KDAC, a company developing histone deacetylase (HDAC) inhibitors, and Novartis, and serves on scientific advisory boards for Pfizer and Eli Lilly and Co.

Correspondence to Mitchell A. Lazar.

Glossary

Lineage-determining transcription factors

Transcription factors that determine the differentiation fate of cells.

Signal-dependent transcription factors

Transcription factors that associate with or bind to specific DNA sequences near lineage-determining transcription factors in response to environmental or physiological cues.

Nuclear receptors

A superfamily of transcription factors that bind to highly specific DNA motifs in direct response to ligand binding to activate or repress gene transcription.

Stoichiometric component

A protein whose interaction with another component of a protein complex is based on their equal molarity.

WD40 repeat-containing proteins

Proteins containing a motif of 40 amino acids that assumes a β-propeller structure and functions in establishing protein–protein interactions, signal transduction and transcription regulation.

Cre recombinase

(Cre). A bacteriophage P1 type I topoisomerase that catalyses DNA recombination between site-specific loxP sites.

Adeno-associated virus

(AAV). A small, non-enveloped, replication-incompetent virus with a small single-stranded DNA genome, which is maintained extrachromosomally and used for gene delivery.

Hepatosteatosis

Fatty liver, often owing to the pathological accumulation of triglycerides.

Nonshivering thermogenesis

A facultative and adaptive process that protects core body temperature.

Oxidative phosphorylation

The transfer of electrons in mitochondria between energy carriers down the electron transport chain to generate a proton gradient and produce ATP.

Global run-on sequencing

(GRO–seq). A nuclear run-on assay coupled to next-generation sequencing to map all transcription by engaged RNA polymerases throughout the genome.

Futile metabolic cycles

Biochemical pathways that operate simultaneously in opposing directions, often leading to the dissipation of energy.

First heart field

(FHF). A developmental structure that gives rise to the cardiac crescent, early cardiac tube and left ventricle.

Second heart field

(SHF). A developmental structure that gives rise to the right ventricle, atrial myocardium and cardiac outflow tract.

Nuclear lamina

A cellular structure adjacent to the inner nuclear membrane that is composed of lamin polymers and other proteins and forms a skeletal nuclear structure that interacts with nuclear scaffold proteins and chromatin.

Facultative heterochromatin

Tightly packed, inaccessible chromatin containing inactive genes, which may become accessible and expressed in certain cell types or following certain cellular cues.

Marfan syndrome

A connective tissue disorder caused by mutations in the fibrillin 1 gene, often presenting as tall, slender individuals with arachnodactyly, cardiac valve disease and predisposition to aortic aneurysm and dissection.

Loeys–Dietz syndrome

A connective tissue disorder with five subtypes, each caused by unique mutations in five genes of the TGFβ signalling pathway, which cause congenital cardiac defects and predisposition to aortic aneurysm and dissection.

CA1 hippocampal region

An area of the brain that is important for memory.

Nucleus accumbens

A region of the brain that is involved in cognitive processing of reward, with neurons containing mostly dopamine receptors; the nucleus accumbens is thought to be the major nucleus involved in addiction.

Paneth cells

Epithelial cells of the small intestine that secrete antimicrobial peptides and proteins, mediate host–microorganism interactions and help defend against enteric pathogens in the gut lumen.

Regulatory T cells

(Treg cells). CD4+, CD25+ and FOXP3+ T cells that suppress the activation of the immune system to maintain tolerance to self-antigens and prevent autoimmune disease.

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Further reading

Fig. 1: HDAC3 is a core component of nuclear receptor co-repressor complexes that modulate nuclear receptor-mediated transcription.
Fig. 2: HDAC3 suppresses liver metabolism and circadian clock genes through distinct enhancer complexes.
Fig. 3: HDAC3 primes thermogenic gene transcription in brown adipose tissue.
Fig. 4: HDAC3 influences cardiac development through deacetylase-independent mechanisms.
Fig. 5: HDAC3 controls brain development, glial cell fate and the formation of long-term memory.
Fig. 6: HDAC3 regulates lung development, intestinal homeostasis, pancreatic β-cell insulin secretion and skeletal muscle metabolism.
Fig. 7: HDAC3 regulates distinct mouse tissue-specific gene expression programmes.