The CHARGE syndrome gene chd-7 plays a role in dauer formation and longevity through autophagy regulation

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

Congreso; Aging, Metabolism, Pathogenesis, Stress, and Small RNAs in C. elegans; 2018

In harsh environments, C. elegans develops into a dauer larva, a stress-resistant and long-lived variant of the L2-stage larva. Although it is known that the nuclear receptor DAF-12 is one of the decisive checkpoints regulating worm aging and dauer formation, the network of genes under its control remain largely uncharacterized. We used chromatin immunoprecipitation to identify DAF-12 target genes and ascertained relevant targets by RNAi screening for dauer suppressors. One of the most potent suppressors was chd-7 (chromodomain helicase DNA-binding protein) which 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(e2144) mutants is impaired by chd-7(gk290). The phenotypes associated with loss of chd-7 function resemble mutations in autophagy genes allowing us to uncover roles for chd-7 and its mammalian ortholog in this process. Electron microscopy as well as biochemical and fluorescent reporters suggest autophagy flux defects upon chd-7 inhibition. HeLa cells expressing the autophagy sensor GFP-LC3 (analogous to worm LGG-1::GFP) also show autophagosomes defects 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 associated 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.