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

Lookup NU author(s): Professor Bob Anderson

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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 Mespl-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. (C) 2015 The Authors. Published by Elsevier Inc.


Publication metadata

Author(s): Payne S, Burney MJ, Mccue K, Popal N, Davidson SM, Anderson RH, Scambler PJ

Publication type: Article

Publication status: Published

Journal: Developmental Biology

Year: 2015

Volume: 405

Issue: 1

Pages: 82-95

Print publication date: 01/09/2015

Online publication date: 21/06/2015

Acceptance date: 17/06/2015

Date deposited: 30/09/2015

ISSN (print): 0012-1606

ISSN (electronic): 1095-564X

Publisher: Academic Press

URL: http://dx.doi.org/10.1016/j.ydbio.2015.06.017

DOI: 10.1016/j.ydbio.2015.06.017


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Funding

Funder referenceFunder name
FS/10/28680British Heart Foundation
RG/15/13/28570British Heart Foundation
PG/12/44/29658British Heart Foundation

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