Dataset Information

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

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.

SUBMITTER: Kargapolova Y

PROVIDER: S-EPMC8140133 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Kargapolova Yulia Y Rehimi Rizwan R Kayserili Hülya H Brühl Joanna J Sofiadis Konstantinos K Zirkel Anne A Palikyras Spiros S Mizi Athanasia A Li Yun Y Yigit Gökhan G Hoischen Alexander A Frank Stefan S Russ Nicole N Trautwein Jonathan J van Bon Bregje B Gilissen Christian C Laugsch Magdalena M Gusmao Eduardo Gade EG Josipovic Natasa N Altmüller Janine J Nürnberg Peter P Längst Gernot G Kaiser Frank J FJ Watrin Erwan E Brunner Han H Rada-Iglesias Alvaro A Kurian Leo L Wollnik Bernd B Bouazoune Karim K Papantonis Argyris A

Nature communications 20210521 1

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 ...[more]

PMID: 34021162

Similar Datasets

Project description:In the field of neurodegenerative diseases, especially sporadic Parkinson's disease (sPD) with dementia (sPDD), the question of how the disease starts and spreads in the brain remains central. While prion-like proteins have been designated as a culprit, recent studies suggest the involvement of additional factors. We found that oxidative stress, damaged DNA binding, cytosolic DNA sensing, and Toll-Like Receptor (TLR)4/9 activation pathways are strongly associated with the sPDD transcriptome, which has dysregulated type I Interferon (IFN) signaling. In sPD patients, we confirmed deletions of mitochondrial (mt)DNA in the medial frontal gyrus, suggesting a potential role of damaged mtDNA in the disease pathophysiology. To explore its contribution to pathology, we used spontaneous models of sPDD caused by deletion of type I IFN signaling (Ifnb-/-/Ifnar-/- mice). We found that the lack of neuronal IFNβ/IFNAR leads to oxidization, mutation, and deletion in mtDNA, which is subsequently released outside the neurons. Injecting damaged mtDNA into mouse brain induced PDD-like behavioral symptoms, including neuropsychiatric, motor, and cognitive impairments. Furthermore, it caused neurodegeneration in brain regions distant from the injection site, suggesting that damaged mtDNA triggers spread of PDD characteristics in an "infectious-like" manner. We also discovered that the mechanism through which damaged mtDNA causes pathology in healthy neurons is independent of Cyclic GMP-AMP synthase and IFNβ/IFNAR, but rather involves the dual activation of TLR9/4 pathways, resulting in increased oxidative stress and neuronal cell death, respectively. Our proteomic analysis of extracellular vesicles containing damaged mtDNA identified the TLR4 activator, Ribosomal Protein S3 as a key protein involved in recognizing and extruding damaged mtDNA. These findings might shed light on new molecular pathways through which damaged mtDNA initiates and spreads PD-like disease, potentially opening new avenues for therapeutic interventions or disease monitoring.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets