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.

Synaptic and Gene Regulatory Mechanisms in Schizophrenia, Autism, and 22q11.2 CNV Mediated Risk for Neuropsychiatric Disorders

“…Given these gene regulatory functions, DGCR8 and HIRA have both been previously hypothesized to play an important role in 22q11.2 CNV phenotypes (67,68). Here, using our disease-informed functional genomic lens, we provide independent, unbiased evidence for the contribution of DGCR8 and HIRA haploinsufficiency to risk for neurodevelopmental disorders.…”

“…DGCR8 is a core component of the microprocessor complex involved in processing miRNAs, which regulate gene expression at the protein level by binding target mRNAs to silence their translation (65). HIRA is a histone chaperone that influences gene expression by facilitating the deposition of the non-canonical histone variant, H3.3, into chromatin (66,67).…”

Histone Chaperones Regulate Mammalian Gene Expression

“…Cardiomyocyte-specific Hira conditional-knockout mice did not disturbed the heart development, but instead resulted in cardiomyocyte hypertrophy and susceptibility to sarcolemmal damage [12]. Cardiomyocyte degeneration led to focal replacement fibrosis and hence resulted in the impaired cardiac function.…”

“…Cardiomyocyte degeneration led to focal replacement fibrosis and hence resulted in the impaired cardiac function. Gene expression profile in Hira conditional-knockout hearts indicated impairment in pathways associated with responses to cellular stress, DNA repair and transcription and could hence implicate HIRA in maintenance of cardiomyocyte homeostasis [12]. HIRA could also individually regulate locus-specific effects on cardiac-specific genes.…”

Reproducibility of histopathological findings in experimental pathology of the mouse: a sorry tail

“…Pathology of genetically engineered mice often requires interpretation of novel findings since each mouse may have unique lesions not previously reported, especially where the study is the first for a novel gene knockout or treatment. A classic example is the relatively common lesion in mouse hearts that pathologists diagnose as epicardial and myocardial mineralization and fibrosis, but non-pathologists often call “dystrophic cardiac calcinosis” or a variety of other names 27–31 . Investigators without pathology backgrounds often over-interpret their research findings, the temptation being to fit results to their hypotheses.…”