NDLI: Cardiomyocyte-specific conditional knockout of the histone chaperone HIRA in mice results in hypertrophy, sarcolemmal damage and focal replacement fibrosis

Content Provider	PubMed Central
Author	Valenzuela, Nicolas Fan, Qiying Faisal, Fa'ak Benjamin, Soibam Harika, Nagandla Liu, Yu Schwartz, Robert J. Mcconnell, Bradley K. Stewart, M. David
Copyright Year	2016
Abstract	HIRA is the histone chaperone responsible for replication-independent incorporation of histone variant H3.3 within gene bodies and regulatory regions of actively transcribed genes, and within the bivalent promoter regions of developmentally regulated genes. The HIRA gene lies within the 22q11.2 deletion syndrome critical region; individuals with this syndrome have multiple congenital heart defects. Because terminally differentiated cardiomyocytes have exited the cell cycle, histone variants should be utilized for the bulk of chromatin remodeling. Thus, HIRA is likely to play an important role in epigenetically defining the cardiac gene expression program. In this study, we determined the consequence of HIRA deficiency in cardiomyocytes in vivo by studying the phenotype of cardiomyocyte-specific Hira conditional-knockout mice. Loss of HIRA did not perturb heart development, but instead resulted in cardiomyocyte hypertrophy and susceptibility to sarcolemmal damage. Cardiomyocyte degeneration gave way to focal replacement fibrosis and impaired cardiac function. Gene expression was widely altered in Hira conditional-knockout hearts. Significantly affected pathways included responses to cellular stress, DNA repair and transcription. Consistent with heart failure, fetal cardiac genes were re-expressed in the Hira conditional knockout. Our results suggest that transcriptional regulation by HIRA is crucial for cardiomyocyte homeostasis.
Related Links	http://dx.doi.org/10.1242/dmm.022889
Ending Page	345
Page Count	11
Starting Page	335
File Format	PDF
ISSN	17548403
e-ISSN	17548411
Journal	Disease Models & Mechanisms
Issue Number	3
Volume Number	9
Language	English
Publisher	The Company of Biologists Ltd
Publisher Date	2016-03-01
Access Restriction	Open
Rights Holder	The Company of Biologists Ltd
Subject Keyword	Immunology and Microbiology (miscellaneous) Biochemistry, Genetics and Molecular Biology(all) Medicine (miscellaneous) Neuroscience (miscellaneous) Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Neuroscience Immunology and Microbiology Medicine Biochemistry, Genetics and Molecular Biology

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