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 Chd7fl/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.
Highlights
CHARGE syndrome is caused by spontaneous loss-of-function mutations to the ATP-dependant chromatin remodeller chromodomain-helicase-DNA-binding protein 7 (CHD7)
CHD7 action lies upstream of key extracellular signalling molecules, including components of the Semaphorin and Slit– Robo pathways, as well as cardiac calcium handling genes, with consequences for excitation–contraction coupling in cardiomyocytes. These results indicate that disruption to CHD7 activity in the cardiogenic mesoderm significantly contributes to the cardiovascular malformations seen in CHARGE patients
We have demonstrated a crucial role for CHD7 activity in the mesodermal lineage for the alignment, septation and maturation of the heart, as well as cardiac innervation, vascularisation, and remodelling of the great vessels
Summary
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. CHD7 action lies upstream of key extracellular signalling molecules, including components of the Semaphorin and Slit– Robo pathways, as well as cardiac calcium handling genes, with consequences for excitation–contraction coupling in cardiomyocytes. Together, these results indicate that disruption to CHD7 activity in the cardiogenic mesoderm significantly contributes to the cardiovascular malformations seen in CHARGE patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
