Deacetylase-independent function of HDAC3 in transcription and metabolism requires nuclear receptor corepressor

TY - JOUR

T1 - Deacetylase-independent function of HDAC3 in transcription and metabolism requires nuclear receptor corepressor

AU - Sun, Zheng

AU - Feng, Dan

AU - Fang, Bin

AU - Mullican, Shannon E

AU - You, Seo-Hee

AU - Lim, Hee-Woong

AU - Everett, Logan J

AU - Nabel, Christopher S

AU - Li, Yun

AU - Selvakumaran, Vignesh

AU - Won, Kyoung-Jae

AU - Lazar, Mitchell A

N1 - Copyright © 2013 Elsevier Inc. All rights reserved.

PY - 2013/12/26

Y1 - 2013/12/26

N2 - Histone deacetylases (HDACs) are believed to regulate gene transcription by catalyzing deacetylation reactions. HDAC3 depletion in mouse liver upregulates lipogenic genes and results in severe hepatosteatosis. Here we show that pharmacologic HDAC inhibition in primary hepatocytes causes histone hyperacetylation but does not upregulate expression of HDAC3 target genes. Meanwhile, deacetylase-dead HDAC3 mutants can rescue hepatosteatosis and repress lipogenic genes expression in HDAC3-depleted mouse liver, demonstrating that histone acetylation is insufficient to activate gene transcription. Mutations abolishing interactions with the nuclear receptor corepressor (NCOR or SMRT) render HDAC3 nonfunctional in vivo. Additionally, liver-specific knockout of NCOR, but not SMRT, causes metabolic and transcriptomal alterations resembling those of mice without hepatic HDAC3, demonstrating that interaction with NCOR is essential for deacetylase-independent function of HDAC3. These findings highlight nonenzymatic roles of a major HDAC in transcriptional regulation in vivo and warrant reconsideration of the mechanism of action of HDAC inhibitors.

AB - Histone deacetylases (HDACs) are believed to regulate gene transcription by catalyzing deacetylation reactions. HDAC3 depletion in mouse liver upregulates lipogenic genes and results in severe hepatosteatosis. Here we show that pharmacologic HDAC inhibition in primary hepatocytes causes histone hyperacetylation but does not upregulate expression of HDAC3 target genes. Meanwhile, deacetylase-dead HDAC3 mutants can rescue hepatosteatosis and repress lipogenic genes expression in HDAC3-depleted mouse liver, demonstrating that histone acetylation is insufficient to activate gene transcription. Mutations abolishing interactions with the nuclear receptor corepressor (NCOR or SMRT) render HDAC3 nonfunctional in vivo. Additionally, liver-specific knockout of NCOR, but not SMRT, causes metabolic and transcriptomal alterations resembling those of mice without hepatic HDAC3, demonstrating that interaction with NCOR is essential for deacetylase-independent function of HDAC3. These findings highlight nonenzymatic roles of a major HDAC in transcriptional regulation in vivo and warrant reconsideration of the mechanism of action of HDAC inhibitors.

KW - Acetylation

KW - Animals

KW - Fatty Liver/enzymology

KW - Gene Expression Profiling/methods

KW - Genotype

KW - HEK293 Cells

KW - Hepatocytes/drug effects

KW - Histone Deacetylase Inhibitors/pharmacology

KW - Histone Deacetylases/chemistry

KW - Histones/metabolism

KW - Humans

KW - Lipid Metabolism/drug effects

KW - Liver/drug effects

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Models, Molecular

KW - Mutation

KW - Nuclear Receptor Co-Repressor 1/genetics

KW - Nuclear Receptor Co-Repressor 2/genetics

KW - Oligonucleotide Array Sequence Analysis

KW - Phenotype

KW - Protein Conformation

KW - Structure-Activity Relationship

KW - Transcription, Genetic/drug effects

KW - Transfection

U2 - 10.1016/j.molcel.2013.10.022

DO - 10.1016/j.molcel.2013.10.022

M3 - Journal article

C2 - 24268577

SN - 1097-2765

VL - 52

SP - 769

EP - 782

JO - Molecular Cell

JF - Molecular Cell

IS - 6

ER -