Chd-7 and autophagy

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

Montevideo

Congreso; First Latin American Worm Meeting; 2017

Institut Pasteur de Montevideo

In harsh environments, the free-living 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 recently 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, 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. Importantly, 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 rare and severe neurodevelopmental disorder with no known treatment. In addition, exome sequencing of patients with autism spectrum disorders (ASDs) has identified recurrent disruptive mutations in Chd8. Despite the public health relevance of these cognitive 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.