The CHARGE syndrome gene chd-7 plays a role in dauer formation and longevity.

DIEGO MARTÍN JOFRÉ; DANE HOFFMAN; ESTEBAN SALVATORE; DONNA STOLZ; TETSU FUKUSHIGE; SIJUNG YUN; MICHAEL W KRAUSE; JUDITH YANOWITZ; DANIEL HOCHBAUM

Congreso; 2nd Latin American Worm Meeting (LAWM); 2020

In harsh environments, C. elegans develops into the dauer larva, a stress-resistant and long-lived variant of the L2-stage larva. The nuclear receptor DAF-12 is one of the decisive checkpoints regulating worm aging and dauer formation, however the genes under its control remain largely uncharacterized. We used chromatin immunoprecipitation to identify DAF-12 regulated genes and ascertained relevant targets by RNAi screening for dauer suppressors. Inhibition of chd-7 (chromodomain helicase DNA-binding protein) leads to developmentally arrested, abnormal dauers that are sensitive to SDS. Notably, deletion alleles chd-7(gk290) and chd-7(tm6139) form abnormal dauers with the same features as chd-7(RNAi), validating our screen. Moreover, chd-7 mutants form reproductive adults in the ts allele daf-7(e1372), suggesting that chd-7 is downstream of both daf-2 and daf-7 signaling for dauer entry. Longevity of daf-2(e1370) and glp-1(e2144) mutants is also impaired in chd-7(gk290). Scanning electron microscopy suggests cuticle defects upon chd-7 inhibition and this was further supported by RNA-Seq analysis. chd-7 shares more that 60% homology with human CHD7/8, which are associated with cognitive disorders, including CHARGE and Kallmann syndromes. Our ability to exploit C. elegans to analyze chd-7 in the context of dauer formation creates an opportunity to identify relevant disease pathways regulated by this class of evolutionarily conserved chromatin modifiers involved.