Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility

Rusty L Montgomery; Christopher A Davis; Matthew J Potthoff; Michael Haberland; Jens Fielitz; Xiaoxia Qi; Joseph A Hill; James A Richardson; Eric N Olson

doi:10.1101/gad.1563807

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Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility

Journal article

Open access

Peer reviewed

Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility

Rusty L Montgomery, Christopher A Davis, Matthew J Potthoff, Michael Haberland, Jens Fielitz, Xiaoxia Qi, Joseph A Hill, James A Richardson and Eric N Olson

Genes & development, Vol.21(14), pp.1790-1802

07/15/2007

DOI: 10.1101/gad.1563807

PMCID: PMC1920173

PMID: 17639084

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Abstract

Histone deacetylases (HDACs) tighten chromatin structure and repress gene expression through the removal of acetyl groups from histone tails. The class I HDACs, HDAC1 and HDAC2, are expressed ubiquitously, but their potential roles in tissue-specific gene expression and organogenesis have not been defined. To explore the functions of HDAC1 and HDAC2 in vivo, we generated mice with conditional null alleles of both genes. Whereas global deletion of HDAC1 results in death by embryonic day 9.5, mice lacking HDAC2 survive until the perinatal period, when they succumb to a spectrum of cardiac defects, including obliteration of the lumen of the right ventricle, excessive hyperplasia and apoptosis of cardiomyocytes, and bradycardia. Cardiac-specific deletion of either HDAC1 or HDAC2 does not evoke a phenotype, whereas cardiac-specific deletion of both genes results in neonatal lethality, accompanied by cardiac arrhythmias, dilated cardiomyopathy, and up-regulation of genes encoding skeletal muscle-specific contractile proteins and calcium channels. Our results reveal cell-autonomous and non-cell-autonomous functions for HDAC1 and HDAC2 in the control of myocardial growth, morphogenesis, and contractility, which reflect partially redundant roles of these enzymes in tissue-specific transcriptional repression.

Morphogenesis

Gene Expression

Pregnancy

Apoptosis

Cell Proliferation

Heart Failure - enzymology

Male

Repressor Proteins - physiology

Heart Defects, Congenital - genetics

Mice, Mutant Strains

Gene Deletion

Heart Defects, Congenital - enzymology

Female

Calcium Channels - genetics

Animals, Newborn

Myocardial Contraction

Fetal Heart - physiology

Histone Deacetylases - genetics

Mice, Inbred C57BL

Heart Defects, Congenital - pathology

Histone Deacetylases - deficiency

Repressor Proteins - genetics

Heart Failure - genetics

Histone Deacetylase 2

Fetal Heart - enzymology

Histone Deacetylase 1

Mice, Knockout

Fetal Heart - growth & development

Muscle Proteins - genetics

Animals

Mice

Histone Deacetylases - physiology

Details

Title: Subtitle: Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility
Creators: Rusty L Montgomery - Department of Molecular Biology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA
Christopher A Davis
Matthew J Potthoff
Michael Haberland
Jens Fielitz
Xiaoxia Qi
Joseph A Hill
James A Richardson
Eric N Olson
Resource Type: Journal article
Publication Details: Genes & development, Vol.21(14), pp.1790-1802
Publisher: United States
DOI: 10.1101/gad.1563807
PMID: 17639084
PMCID: PMC1920173
ISSN: 0890-9369
eISSN: 1549-5477
Language: English
Date published: 07/15/2007
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984040494602771

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