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

Yulia Kargapolova,Stefan Frank,Gernot Längst,Hülya Kayserili,Eduardo Gade Gusmao,Janine Altmüller,Joanna Brühl,Peter Nürnberg,Erwan Watrin,Rizwan Rehimi,Bregje W.m Van Bon ,Athanasia Mizi,Álvaro Rada-Iglesias ,Bernd Wollnik,Spyridon Palikyras ,Konstantinos Sofiadis,Christian Gilissen,Han G Brunner ,Leo Kurian,Frank J Kaiser,Karim Bouazoune,Nataša Josipović ,Magdalena Laugsch,Yun Li,Anne Zirkel,Gökhan Yiğit ,Jonathan Trautwein,Alexander Hoischen,Nicole Russ,Argyris Papantonis

doi:10.1038/s41467-021-23327-1

Abstract

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.

Highlights

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
Despite the rarity of Hallermann-Streiff syndrome (HSS) samples, whole-exome sequencing of blood and saliva-derived DNA from a patient and parents uncovered a single de novo missense mutation resulting in an isoleucine to methionine (I1600M) amino acid exchange in the CHD6 coding sequence
We exploited a CHD6 de novo mutation linked to the rare Hallermann-Streiff syndrome to model the disease using isogenic induced pluripotent stem cell (iPSC) lines and investigate the roles of this understudied remodeler

Summary

Introduction

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. 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. Human cells continuously face genotoxic stress throughout development, and mechanisms are in place to survey and restore any resulting DNA damage Weakening of these mechanisms leads to DNA damage accumulation and is understood to cause premature ageing syndromes (known as segmental progerias)[22]. The well-studied Hutchinson-Gilford and Werner progerias stem from mutations in LMNA and RECQL2, respectively, which promote genome instability[23,24]

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Results

Conclusion