title: HIRA Is Required for Heart Development and Directly Regulates Tnni2 and Tnnt3.
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.
authors: Developmental Biology of Birth Defects Section, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, United Kingdom.
authors: Daniel
authors: D
authors: Dilg
authors: Developmental Biology of Birth Defects Section, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, United Kingdom.|Faculty of Medicine, Alexandria University, El-Gaish Rd, Alexandria, Egypt.
authors: Rasha Noureldin M
authors: RN
authors: Saleh
authors: Developmental Biology of Birth Defects Section, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, United Kingdom.
authors: Sarah Elizabeth Lee
authors: SE
authors: Phelps
authors: Developmental Biology of Birth Defects Section, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, United Kingdom.
authors: Yoann
authors: Y
authors: Rose
authors: The Francis Crick Institute, Mill Hill Laboratory, the Ridgeway, Mill Hill, London NW7 1AA, United Kingdom.
authors: Laurent
authors: L
authors: Dupays
authors: UCL Genetics Institute (UGI) Department of Genetics, Environment and Evolution University College London, Gower St, London WC1E 6BT, United Kingdom.
authors: Cian
authors: C
authors: Murphy
authors: Faculty of Medicine, Alexandria University, El-Gaish Rd, Alexandria, Egypt.
authors: Timothy
authors: T
authors: Mohun
authors: Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, United Kingdom.
authors: Robert H
authors: RH
authors: Anderson
authors: Developmental Biology of Birth Defects Section, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, United Kingdom.
authors: Peter J
authors: PJ
authors: Scambler
authors: Developmental Biology of Birth Defects Section, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, United Kingdom.
authors: Ariane L A
authors: AL
authors: Chapgier
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000502:physiology*; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006321:Heart / Q000196:embryology*; D056488:Histone Chaperones / Q000502:physiology*; D000072576:Homeobox Protein Nkx-2.5 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D014336:Troponin / Q000235:genetics / Q000378:metabolism*; D019210:Troponin I / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C484187:Hira protein, mouse; D056488:Histone Chaperones; D000072576:Homeobox Protein Nkx-2.5; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors; D014336:Troponin; D019210:Troponin I; C587363:troponin T3, skeletal, fast, mouse