title: Cardiomyocyte-specific conditional knockout of the histone chaperone HIRA in mice results in hypertrophy, sarcolemmal damage and focal replacement fibrosis.
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.
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Valenzuela
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA.
authors.forename: Qiying
authors.initials: Q
authors.lastname: Fan
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA.
authors.forename: Faisal
authors.initials: F
authors.lastname: Fa'ak
authors.affiliation: Department of Computer Science and Engineering Technology, University of Houston-Downtown, Houston, TX 77002, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Soibam
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
authors.forename: Harika
authors.initials: H
authors.lastname: Nagandla
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA Stem Cell Engineering Department, Texas Heart Institute at St Luke's Episcopal Hospital, Houston, TX 77030, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwartz
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA.
authors.forename: Bradley K
authors.initials: BK
authors.lastname: McConnell
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA dstewart@uh.edu.
authors.forename: M David
authors.initials: MD
authors.lastname: Stewart
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D018797:Cell Cycle Proteins / Q000172:deficiency* / Q000378:metabolism; D049109:Cell Proliferation; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D005333:Fetus / Q000378:metabolism; D005786:Gene Expression Regulation; D006334:Heart Function Tests; D056488:Histone Chaperones / Q000172:deficiency* / Q000378:metabolism; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity; D018384:Oxidative Stress / Q000235:genetics; D015203:Reproducibility of Results; D012508:Sarcolemma / Q000378:metabolism* / Q000473:pathology*; D013312:Stress, Physiological / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency* / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C484187:Hira protein, mouse; D056488:Histone Chaperones; D014157:Transcription Factors
keywords: Cardiomyocyte; H3.3; HIRA; Heart; Histone