Maintenance of adult cardiac function requires the chromatin factor Asxl2

Abstract During development and differentiation, cell type-specific chromatin configurations are set up to facilitate cell type-specific gene expression. Defects in the establishment or the maintenance of the correct chromatin configuration have been associated with diseases ranging from leukemia to...

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Bibliographic Details
Published in:Journal of molecular and cellular cardiology 2012-11, Vol.53 (5), p.734-741
Main Authors: Lai, Hsiao-Lei, Grachoff, Milana, McGinley, Andrea L, Khan, Farida F, Warren, Chad M, Chowdhury, Shamim A.K, Wolska, Beata M, Solaro, R. John, Geenen, David L, Wang, Q. Tian
Format: Article
Language:English
Subjects:
Animals
Blood Pressure
Cardiomyopathy, Dilated - metabolism
Cardiomyopathy, Dilated - pathology
Cardiomyopathy, Dilated - physiopathology
Cardiovascular
Case-Control Studies
Cell Size
Chromatin factor
Cyclic AMP-Dependent Protein Kinases - metabolism
Enhancer of Zeste Homolog 2 Protein
Female
Gene Expression Regulation
HEK293 Cells
Histone methylation
Human heart disease etiology
Humans
Male
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Myocardium - enzymology
Myocardium - metabolism
Myocardium - pathology
Myocytes, Cardiac - enzymology
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - physiology
Myosin Heavy Chains - genetics
Myosin Heavy Chains - metabolism
Phosphorylation
Polycomb Repressive Complex 2 - metabolism
Promoter Regions, Genetic
Protein Processing, Post-Translational
Repressor Proteins - genetics
Repressor Proteins - metabolism
Signal Transduction
Stroke Volume
Troponin I - metabolism
Ventricular dysfunction
Ventricular Function
β-MHC de-repression
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Summary:Abstract During development and differentiation, cell type-specific chromatin configurations are set up to facilitate cell type-specific gene expression. Defects in the establishment or the maintenance of the correct chromatin configuration have been associated with diseases ranging from leukemia to muscular dystrophy. The heart expresses many chromatin factors, and we are only beginning to understand their roles in heart development and function. We have previously shown that the chromatin regulator Asxl2 is highly expressed in the murine heart both during development and adulthood. In the absence of Asxl2, there is a significant reduction in trimethylation of histone H3 lysine 27 (H3K27), a histone mark associated with lineage-specific silencing of developmental genes. Here we present evidence that Asxl2 is required for the long-term maintenance of ventricular function and for the maintenance of normal cardiac gene expression. Asxl2 −/− hearts displayed progressive deterioration of ventricular function. By 10 months of age, there was ~ 37% reduction in fractional shortening in Asxl2 −/− hearts compared to wild-type. Analysis of the expression of myofibril proteins suggests that Asxl2 is required for the repression of β-MHC. Asxl2 −/− hearts did not exhibit hypertrophy, suggesting that the de-repression of β-MHC was not the result of hypertrophic response. Instead, Asxl2 and the histone methyltansferase Ezh2 co-localize to β-MHC promoter, suggesting that Asxl2 directly represses β-MHC. Interrogation of the CardioGenomics database revealed that ASXL2 is down-regulated in the hearts of patients with ischemic or idiopathic dilated cardiomyopathy. We propose that chromatin factors like Asxl2 function in the adult heart to regulate cell type- and stage-specific patterns of gene expression, and the disruption of such regulation may be involved in the etiology and/or development of certain forms of human heart disease.
ISSN:0022-2828
1095-8584
DOI:10.1016/j.yjmcc.2012.08.014