The CHARGE syndrome ortholog CHD-7 regulates TGF-b pathways in C. elegans

JOFRÉ, DM; HOFFMAN, DK; CERVINO, AS; HAHN, GM; GRUNDY, MK; YUN, S; AMRIT, FRG; STOLZ, DB; GODOY, LF; SALVATORE, E; ROSSI, FA; GHAZI, A; CIRIO, MC; YANOWITZ, JUDITH L; HOCHBAUM, DANIEL

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Año: 2022 vol. 119

0027-8424

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. Despite the public health relevance of this disorder, relevant cellular pathways, and 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, stress response and body size determination. Consistent with our discoveries, we found chd-7 to be allelic to scd-3, a previously identified dauer suppressor from the DAF-7/TGF-b pathway. Epistatic analysis places CHD-7 at the level of the DAF-3/DAF-5 complex, but we found that CHD-7 also directly impacts the expression of multiple components of this pathway. Transcriptomic analysis revealed that chd-7 mutants fail to repress daf-9 for execution of the dauer program. In addition, CHD-7 regulates the DBL-1/BMP pathway components and shares roles in male tail development and cuticle synthesis. To explore a potential 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 a reduction in col2a1 mRNA levels, a collagen whose expression depends on TGF-b signaling. Both embryonic lethality and craniofacial defects in Chd7-depleted tadpoles were partially rescued by over-expression of col2a1 mRNA. We suggest that Chd7 has conserved roles in regulation of the TGF-b signaling pathway and pathogenic Chd7 could lead to a defective extracellular matrix deposition.