C. elegans as a model to study CHD-dependent disorders

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

Conferencia; Buenos Aires Research Conferences on Autophagy 2017; 2017

Epigenetic impairment is a recurring mechanism in the etiology of many cognitive syndromes. CHARGE and Kallmann, two multisystemic neurodevelopmental disorders are caused by mutations in the chromodomain helicase Chd7. In addition, disruptive mutations in the related protein Chd8 has been identified in patients with autism spectrum disorders (ASD). Despite the public health relevance of these cognitive disorders, little is known about the function of these enzymes in disease pathology. We identified chd-7, the Caenorhabditis elegans functional ortholog of hCHD7/8 in an RNAi screen for suppressors of dauer formation. 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. Electron microscopy images reveal autophagosome accumulation, a result that is further supported by biochemical analyses. Importantly, KEGG analysis reveals that the lysosome is the most downregulated pathway in Chd7−/− ES cells, providing the molecular basis for autophagy dysfunction. Thus, our data suggests a conserved role for chd-7/Chd7 in autophagy regulation and provide the first druggable pathway to improve treatment for these patients.