title: 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 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.
authors.affiliation: Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA. hlai4@uic.edu
authors.forename: Hsiao-Lei
authors.initials: HL
authors.lastname: Lai
authors.forename: Milana
authors.initials: M
authors.lastname: Grachoff
authors.forename: Andrea L
authors.initials: AL
authors.lastname: McGinley
authors.forename: Farida F
authors.initials: FF
authors.lastname: Khan
authors.forename: Chad M
authors.initials: CM
authors.lastname: Warren
authors.forename: Shamim A K
authors.initials: SA
authors.lastname: Chowdhury
authors.forename: Beata M
authors.initials: BM
authors.lastname: Wolska
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
authors.forename: David L
authors.initials: DL
authors.lastname: Geenen
authors.forename: Q Tian
authors.initials: QT
authors.lastname: Wang
mesh_terms: D000818:Animals; D001794:Blood Pressure; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016022:Case-Control Studies; D048429:Cell Size; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013318:Stroke Volume; D019210:Troponin I / Q000378:metabolism; D016276:Ventricular Function
chemical_list: C484296:ASXL2 protein, mouse; C551613:Myh7 protein, mouse; D012097:Repressor Proteins; D019210:Troponin I; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; D017868:Cyclic AMP-Dependent Protein Kinases; D018995:Myosin Heavy Chains