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A critical role for the chromatin remodeller CHD7 in anterior mesoderm during cardiovascular development
Sophie Payne1, Matthew J Burney1, Karen McCue1
1Developmental Biology of Birth Defects Section, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
Insights
CHARGE syndrome, caused by CHD7 mutations, involves heart defects. New findings show CHD7 is crucial in anterior mesoderm for heart development, innervation, and function.
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Genetics
Background:
- CHARGE syndrome is linked to CHD7 mutations, affecting development and causing congenital anomalies like heart malformations.
- Previous research highlighted neural crest disruption in CHARGE syndrome etiology.
- The role of CHD7 in anterior mesoderm during heart development was not fully understood.
Purpose of the Study:
- To investigate the role of CHD7 in the Mesp1-expressing anterior mesoderm during heart development.
- To identify the molecular mechanisms underlying CHD7's function in cardiovascular development.
- To explore CHD7's impact on cardiac innervation and cardiomyocyte function.
Main Methods:
- Conditional ablation of Chd7 in Mesp1-expressing anterior mesoderm.
- Analysis of cardiovascular defects, cardiac innervation, and embryonic lethality.
- Genome-wide transcriptional analysis and chromatin immunoprecipitation (ChIP) assays.
- Investigation of calcium handling genes and excitation-contraction coupling.
Main Results:
- Conditional Chd7 ablation in anterior mesoderm caused severe cardiovascular defects and loss of cardiac innervation, leading to embryonic lethality.
- Aberrant expression of Class 3 Semaphorin and Slit-Robo signaling pathways was observed.
- CHD7 was found to localize at the Sema3c promoter, influencing chromatin structure and suggesting direct transcriptional regulation.
- A novel role for CHD7 in regulating calcium handling genes and excitation-contraction coupling in cardiomyocytes was identified.
Conclusions:
- CHD7 is essential in the cardiogenic mesoderm for multiple cardiovascular development processes.
- CHD7 regulates cardiac structure, innervation, and cardiomyocyte function.
- These findings reveal new insights into CHARGE syndrome pathogenesis and 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.
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