The Chromatin Remodeller CHD7 Lies Upstream of Semaphorin, Slit/Robo and Calcium Handling Pathways during Cardiovascular Development. Mus musculus

Chromatin remodelling provides a key mechanism for the regulation of gene expression through dynamic alterations in nucleosome occupancy at promoters and enhancers. Haploinsufficiency for the ATP-dependent chromatin remodeller chromodomain-helicase-DNA-binding protein 7 (CHD7) causes human CHARGE syndrome. CHARGE is characterised by a distinct pattern of congenital anomalies, including cardiovascular malformations, and has traditionally been considered a neurocristopathy. We present a new perspective, by showing severe structural cardiovascular defects following ablation of Chd7 in the anterior mesoderm and other cardiac-related lineages. We identify multiple downstream pathways affected by the loss of Chd7 and disruption of excitation-contraction coupling in cardiomyocytes. Furthermore, we demonstrate CHD7 binding at the Sema3C promoter and alterations to the local chromatin structure in vivo, indicating direct transcriptional regulation. This work therefore provides novel insights into the etiology of heart defects arising in CHARGE syndrome and reveals a requirement for CHD7 activity in mesodermal cardiac progenitors. Overall design: We performed microarrays on whole hearts dissected from E11.5 and E13.5 embryos, resulting from crossing Chd7fl/+;Mesp1-Cre mice with Chd7fl/fl mice. This ablates Chd7 expression specifically in the mesoderm, from which the heart derives.