title: A critical role for the chromatin remodeller CHD7 in anterior mesoderm during cardiovascular development.
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.
authors.affiliation: Developmental Biology of Birth Defects Section, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Payne
authors.affiliation: Developmental Biology of Birth Defects Section, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Burney
authors.affiliation: Developmental Biology of Birth Defects Section, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: McCue
authors.affiliation: Developmental Biology of Birth Defects Section, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Nelo
authors.initials: N
authors.lastname: Popal
authors.affiliation: The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Davidson
authors.affiliation: Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Anderson
authors.affiliation: Developmental Biology of Birth Defects Section, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK. Electronic address: p.scambler@ucl.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000196:embryology / Q000473:pathology; D020013:Calcium Signaling / Q000235:genetics; D002319:Cardiovascular System / Q000196:embryology* / Q000294:innervation / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020964:Embryo Loss / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000473:pathology; D004699:Endocardium / Q000002:abnormalities / Q000473:pathology; D056966:Excitation Contraction Coupling / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D019426:Integrases / Q000378:metabolism; D008297:Male; D008648:Mesoderm / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D039961:Semaphorins / Q000378:metabolism
chemical_list: C507367:Chd7 protein, mouse; D004268:DNA-Binding Proteins; D039961:Semaphorins; C045073:Cre recombinase; D019426:Integrases
keywords: CHARGE syndrome; Chromatin remodelling; Congenital heart defects; Heart development