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A critical role for the chromatin remodeller CHD7 in anterior mesoderm during cardiovascular development

Payne, S; Burney, MJ; McCue, K; Popal, N; Davidson, SM; Anderson, RH; Scambler, PJ; (2015) A critical role for the chromatin remodeller CHD7 in anterior mesoderm during cardiovascular development. Developmental Biology , 405 (1) pp. 82-95. 10.1016/j.ydbio.2015.06.017. Green open access

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Abstract

CHARGE syndrome is caused by spontaneous loss-of-function mutations to the ATP-dependant chromatin remodeller chromodomain-helicase-DNA-binding protein 7 (CHD7). It is characterised by a distinct pattern of congenital anomalies, including cardiovascular malformations. Disruption to the neural crest lineage has previously been emphasised in the aetiology of this developmental disorder. We present evidence for an additional requirement for CHD7 activity in the Mesp1-expressing anterior mesoderm during heart development. Conditional ablation of Chd7 in this lineage results in major structural cardiovascular defects akin to those seen in CHARGE patients, as well as a striking loss of cardiac innervation and embryonic lethality. Genome-wide transcriptional analysis identified aberrant expression of key components of the Class 3 Semaphorin and Slit-Robo signalling pathways in Chd7(fl/fl);Mesp1-Cre mutant hearts. CHD7 localises at the Sema3c promoter in vivo, with alteration of the local chromatin structure seen following Chd7 ablation, suggestive of direct transcriptional regulation. Furthermore, we uncover a novel role for CHD7 activity upstream of critical calcium handling genes, and demonstrate an associated functional defect in the ability of cardiomyocytes to undergo excitation-contraction coupling. This work therefore reveals the importance of CHD7 in the cardiogenic mesoderm for multiple processes during cardiovascular development.

Type: Article
Title: A critical role for the chromatin remodeller CHD7 in anterior mesoderm during cardiovascular development
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ydbio.2015.06.017
Publisher version: http://dx.doi.org/10.1016/j.ydbio.2015.06.017
Language: English
Additional information: © 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Keywords: CHARGE syndrome, Chromatin remodelling, Congenital heart defects, Heart development, Animals, Blood Vessels, Calcium Signaling, Cardiovascular System, Chromatin Assembly and Disassembly, Crosses, Genetic, DNA-Binding Proteins, Embryo Loss, Embryo, Mammalian, Endocardium, Excitation Contraction Coupling, Female, Gene Deletion, Gene Expression Regulation, Developmental, Integrases, Male, Mesoderm, Mice, Myocytes, Cardiac, Oligonucleotide Array Sequence Analysis, Semaphorins
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 Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science
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: https://discovery.ucl.ac.uk/id/eprint/1472415
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