chd-7 and autophagy

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

Congreso; Latin American Worm Meeting 2017; 2017

In harsh environments, C. elegans develops into a dauer larva, a stress-resistant and long-lived variant of the L2-stage larva1. The nuclear receptor DAF-12 plays roles in worm aging and is required for dauer formation2. We recently identified DAF-12 target genes by chromatin immunoprecipitation3. 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. Notably, chd-7(gk290) forms abnormal dauers with the same features as chd-7(RNAi), validating our screen. In addition, the longevity of daf-2(e1370) and glp-1(e2141) mutants is impaired by chd-7(gk290). 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, chd-7(gk290) worms, expressing the autophagy sensor GFP::LGG-1, accumulate abnormal autophagosomes. 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 cognitive disorders, including CHARGE and Kallmann syndromes. Despite the public health burden of these disorders, functionally relevant targets of CHD7/8 that relate to disease pathology are still poorly understood. 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 involved in disease progression.