PT  - JOURNAL ARTICLE
AU  - Diego Martín Jofré
AU  - Dane Kristian Hoffman
AU  - Ailen S. Cervino
AU  - McKenzie Grundy
AU  - Sijung Yun
AU  - Francis Raj Gandhi Amrit
AU  - Donna Beer Stolz
AU  - Esteban Salvatore
AU  - Fabiana Alejandra Rossi
AU  - Arjumand Ghazi
AU  - M. Cecilia Cirio
AU  - Judith L. Yanowitz
AU  - Daniel Hochbaum
TI  - ANALYSIS OF CHD-7 DEFECTIVE DAUER NEMATODES IMPLICATES COLLAGEN MISREGULATION IN CHARGE SYNDROME FEATURES
AID  - 10.1101/2021.03.26.437191
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.03.26.437191
4099  - http://biorxiv.org/content/early/2021/03/26/2021.03.26.437191.short
4100  - http://biorxiv.org/content/early/2021/03/26/2021.03.26.437191.full
AB  - CHARGE syndrome is a complex developmental disorder caused by mutations in the chromodomain helicase DNA-binding protein7 (CHD7) and characterized by retarded growth and malformations in the heart and nervous system. However, despite the public health relevance of this disorder, relevant targets of CHD7 that relate to disease pathology are still poorly understood. Here we report that chd-7, the nematode ortholog of CHD7, is required for dauer morphogenesis, lifespan determination, and stress response. Genetic epistasis placed chd-7 in the TGF-β pathway. Consistent with our discoveries, we found chd-7 to be allelic to scd-3, a previously identified dauer suppressor from the TGF-β pathway. Interestingly, DAF-12 transcriptionally upregulated chd-7, which is necessary to repress daf-9 for execution of the dauer program. Transcriptomic analysis comparing chd-7–defective and normal dauers showed enrichment of collagen genes, consistent with a conserved role for the TGF-β pathway in expression of the extracellular matrix. To validate a conserved function for chd-7 in vertebrates, we used Xenopus laevis embryos, an established model to study craniofacial development. Morpholino mediated knockdown of Chd7 led to embryonic lethality, a reduction in col2a1 mRNA levels and craniofacial defects in tadpoles. Both lethality and malformations were partially rescued in Chd7-depleted embryos by over-expression of col2a1. We suggest that pathogenic features of CHARGE syndrome caused by Chd7 mutations, such as craniofacial malformations, result from the reduction of collagen levels. These studies establish C. elegans as an amenable animal model to study the etiology of the developmental defects associated with pathogenic Chd7.Competing Interest StatementThe authors have declared no competing interest.