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

Dilg, D; Saleh, RNM; Phelps, SEL; Rose, Y; Dupays, L; Murphy, C; Mohun, T; ... Chapgier, ALA; + view all (2016) HIRA Is Required for Heart Development and Directly Regulates Tnni2 and Tnnt3. PLOS ONE , 11 (8) 10.1371/journal.pone.0161096. Green open access

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Abstract

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.

Type: Article
Title: HIRA Is Required for Heart Development and Directly Regulates Tnni2 and Tnnt3
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0161096
Publisher version: http://dx.doi.org/10.1371/journal.pone.0161096
Language: English
Additional information: © 2016 Dilg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, WOLF-HIRSCHHORN-SYNDROME, HISTONE H3.3 DEPOSITION, SYNDROME CANDIDATE GENE, CHROMATIN LANDSCAPE, IN-VIVO, TRANSCRIPTION, CHAPERONE, MOUSE, SKELETAL, NKX2-5
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Development Bio and Cancer Prog
URI: http://discovery.ucl.ac.uk/id/eprint/1512193
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