Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology

© The Author(s) 2021.
Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers implicated in human pathologies, with CHD6 being one of its least studied members. We discovered a de novo CHD6 missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. By combining genomics with functional in vivo and in vitro assays, we show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS mutation affects CHD6 protein folding and impairs its ability to recruit co-remodelers in response to DNA damage or autophagy stimulation. This leads to accumulation of DNA damage burden and senescence-like phenotypes. We therefore uncovered a molecular mechanism explaining HSS onset via chromatin control of autophagic flux and genotoxic stress surveillance.
This work was supported by UKGM (Project 5/2016), by the Deutsche Forschungsgemeinschaft via TRR81 (Project 109546710) and CCRC2407 (Project 360043781), as well as by an Else-Kroener-Fresenius-Stiftung “Key-Project” grant (Project 2015_A125). Y.K. was further supported by the TRR259 (Project 397484323), and S.P. and N.J. by the International Max Planck Research School for Genome Science, part of the GAUSS/GGNB. Open Access funding enabled and organized by Projekt DEAL.