Journal Article

HIRA Is Required for Heart Development and Directly Regulates Tnni2 and Tnnt3

Mohun, Timothy, Dilg, Daniel, Saleh, Rasha Noureldin M., Murphy, Cian, Chapgier, Ariane L. A., Dupays, Laurent, Anderson, Robert H., Phelps, Sarah Elizabeth Lee, Rose, Yoann, Scambler, Peter J.

2016

Overview

Chromatin remodelling is essential for cardiac development. Interestingly, the role of histone chaperones has not been investigated in this regard. HIRA is a member of the HUCA (HIRA/UBN1/CABIN1/ASF1a) complex that deposits the variant histone H3.3 on chromatin independently of replication. Lack of HIRA has general effects on chromatin and gene expression dynamics in embryonic stem cells and mouse oocytes. Here we describe the conditional ablation of Hira in the cardiogenic mesoderm of mice. We observed surface oedema, ventricular and atrial septal defects and embryonic lethality. We identified dysregulation of a subset of cardiac genes, notably upregulation of troponins Tnni2 and Tnnt3, involved in cardiac contractility and decreased expression of Epha3, a gene necessary for the fusion of the muscular ventricular septum and the atrioventricular cushions. We found that HIRA binds GAGA rich DNA loci in the embryonic heart, and in particular a previously described enhancer of Tnni2/Tnnt3 (TTe) bound by the transcription factor NKX2.5. HIRA-dependent H3.3 enrichment was observed at the TTe in embryonic stem cells (ESC) differentiated toward cardiomyocytes in vitro. Thus, we show here that HIRA has locus-specific effects on gene expression and that histone chaperone activity is vital for normal heart development, impinging on pathways regulated by an established cardiac transcription factor.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Biology and Life Sciences / Birth defects / Cabin1 protein / Cardiomyocytes / Cell Cycle Proteins - physiology / Cell Differentiation / Cell Lineage / Cells, Cultured / Chaperones / Childrens health / Chromatin / Chromatin remodeling / Cushions / Deoxyribonucleic acid / Developmental biology / DNA / Edema / Embryo cells / Embryo, Mammalian - cytology / Embryo, Mammalian - metabolism / Embryonic development / Embryonic stem cells / Embryonic Stem Cells - cytology / Embryonic Stem Cells - metabolism / Gene expression / Gene Expression Regulation / Gene fusion / Genetics / Genomes / Heart / Heart - embryology / Heart diseases / Histone Chaperones - physiology / Histone H3 / Homeobox Protein Nkx-2.5 - genetics / Homeobox Protein Nkx-2.5 - metabolism / Kinases / Lethality / Loci / Medicine / Medicine and Health Sciences / Mesoderm / Mice / Mice, Knockout / Morphogenesis / Muscle contraction / Myocytes, Cardiac - cytology / Myocytes, Cardiac - metabolism / Nkx2.5 protein / Oocytes / Physiology / Rodents / Septum / Stem cell transplantation / Stem cells / Transcription Factors - physiology / Troponin - genetics / Troponin - metabolism / Troponin I - genetics / Troponin I - metabolism / Ventricle