Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology
Résumé
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. © 2021, The Author(s).
Mots clés
chemical binding
DNA
enzyme activity
gene expression
genomics
pathology
protein
CHD6 protein
human
DNA binding protein
DNA helicase
nerve protein
autophagy
chromatin
chromatin assembly and disassembly
DNA damage
epigenetics
gene editing
genetics
Hallermann Streiff syndrome
metabolism
mutation
phenotype
physiology
Autophagy
Chromatin
Chromatin Assembly and Disassembly
DNA Damage
DNA Helicases
DNA-Binding Proteins
Epigenomics
Gene Editing
Gene Expression
Hallermann's Syndrome
Humans
Mutation
Nerve Tissue Proteins
Phenotype
Domaines
Sciences du Vivant [q-bio]
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