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Series GSE30076 Query DataSets for GSE30076
Status Public on Dec 31, 2011
Title Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis
Organism Mus musculus
Experiment type Expression profiling by array
Summary Adult-onset diseases can be associated with in utero events, but mechanisms for such temporally distant dysregulation of organ function remain unknown. The polycomb histone methyltransferase, Ezh2, stabilizes transcription by depositing repressive histone marks during development that persist into adulthood, but the function of Ezh2-mediated transcriptional stability in postnatal organ homeostasis is not understood. Here, we show that Ezh2 stabilizes the postnatal cardiac gene expression program and prevents cardiac pathology, primarily by repressing the homeodomain transcription factor Six1 in differentiating cardiac progenitors. Loss of Ezh2 in embryonic cardiac progenitors, but not in differentiated cardiomyocytes, resulted in postnatal cardiac pathology, including cardiomyocyte hypertrophy and fibrosis. Loss of Ezh2 caused broad derepression of skeletal muscle genes, including the homeodomain transcription factor Six1, which is expressed in cardiac progenitors but is normally silenced upon cardiac differentiation. Many of the deregulated genes are direct Six1 targets, implying a critical requirement for stable repression of Six1 in cardiac myocytes. Indeed, upon de-repression, Six1 promotes cardiac pathology, as it was sufficient to induce cardiac hypertrophy. Furthermore, genetic reduction of Six1 levels almost completely rescued the pathology of Ezh2-deficient hearts. Thus, repression of a single transcription factor in cardiac progenitors by Ezh2 is essential for stability of the adult heart gene expression program and homeostasis. Our results suggest that epigenetic dysregulation during discrete developmental windows can predispose to adult disease and dysregulated stress responses.
 
Overall design Global gene expression profiles of Ezh2-deficient hearts. The right ventricle and the interventricular septum of five wild type (Ezh2f/f) and four Ezh2-deficient (Ezh2f/f;Mef2cAHF::Cre) mice were analyzed.
 
Contributor(s) Bruneau B, Delgado P
Citation(s) 22267199
Submission date Jun 17, 2011
Last update date Mar 04, 2019
Contact name Alisha Holloway
E-mail(s) alisha.holloway@gladstone.ucsf.edu
Organization name Gladstone Institutes
Street address 1650 Owens Street
City San Francisco
State/province CA
ZIP/Postal code 94158
Country USA
 
Platforms (1)
GPL6246 [MoGene-1_0-st] Affymetrix Mouse Gene 1.0 ST Array [transcript (gene) version]
Samples (9)
GSM744482 e4 Ez f/wt
GSM744483 e5 Ez f/wt
GSM744484 3x' Ez f/wt
Relations
BioProject PRJNA144097

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Supplementary file Size Download File type/resource
GSE30076_RAW.tar 40.0 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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