THE C. elegans DAUER LARVA UNCOVERS A ROLE FOR CHD7/8 IN AUTOPAGHY REGULATION

DIEGO MARTÍN JOFRÉ; ESTEBAN SALVATORE; FABIANA ROSSI; MARIO ROSSI; DONNA STOLZ; JUDITH YANOWITZ; DANIEL HOCHBAUM

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

In harsh environments, the nematode C. elegans develops into a dauer larva, a stress-resistant, metabolically altered and long-lived variant of the L2-stage larva. The nuclear hormone receptor DAF-12 plays important roles in development and aging and is required for dauer formation. We identified DAF-12 target genes by chromatin immunoprecipitation. To address the relevance of these genes, we conducted an RNAi screen for dauer suppressors. Inhibition of chd-7 (chromodomain helicase DNA-binding protein) leads to developmentally arrested, abnormal dauers that are sensitive to SDS and have impaired fat accumulation. Notably, the allele chd-7(gk290) forms abnormal dauers with these same features, validating our screen. Longevity of daf-2(e1370) and glp-1(e2144) mutants is significantly impaired by chd-7(gk290) and chd-7 overexpression increases lifespan. Loss of chd-7 function resembled mutations in autophagy genes allowing us to uncover roles for chd-7 and its mammalian ortholog in this process. Specifically, both chd-7(gk290) worms expressing the autophagy sensor GFP::LGG-1 and electron micrographs of daf-2(e1370);chd-7(gk290) mutants display abnormal autophagosome accumulation. Hela cells expressing the related autophagy sensor GFP-LC3 also show abnormal autophagosomes upon Chd7 knockdown, suggesting a conserved role for Chd7 in autophagy regulation. Based on structural and sequence conservation, CHD-7 shares more that 60% homology with human CHD7 and CHD8, which are related with a spectrum of human disease phenotypes. Mutations in Chd7 are associated with CHARGE syndrome, a neurodevelopmental disorder with no known treatment and disruptive mutations in Chd8 have been related with autism spectrum disorders (ASDs). Our ability to exploit C. elegans to analyze chd-7 in the context of dauer formation creates an opportunity to identify relevant pathways misregulated by this class of evolutionarily conserved chromatin modifiers.