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Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology [ATAC-Seq]

ABSTRACT: Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology [ATAC-Seq]

PROVIDER: PRJNA675611 | ENA |

REPOSITORIES: ENA

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Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology [ATAC-Seq]

Project description:Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers critically implicated in human pathologies, with CHD6 being one of its least studied members. Here, 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. 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-factors in response to DNA damage or autophagy stimulation. This leads to an accumulation of DNA damage burden and to senescence-like phenotypes. By combining genomics and functional assays, we describe for the first time a molecular mechanism for the chromatin control of autophagic flux and genotoxic stress surveillance that applies broadly to human cell types and explains HSS onset.

2021-02-22 | GSE161118 | GEO

Impaired CHD6 function links misregulation of autophagy and DNA damage response to premature ageing [ChIP-Seq]

Project description:Members of the Chromodomain-Helicase-DNA binding (CHD) protein family are chromatin remodelers critically implicated in human pathologies. CHD6 is the least studied member of this family, and we were motivated to dissect its in-cell roles by discovering a mutated CHD6 allele in a patient suffering from the rare Hallermann-Streiff premature aging syndrome (HSS). We generated isogenic iPSC lines carrying (or not) this single point mutation in the CHD6 SANT/SLIDE domain, which allow studying HSS-relevant cell identities. Using these lines, we show for the first time that CHD6 binds the promoters of a cohort of autophagy and stress response genes across cell types. This CHD6 mutation impairs its ability to recruit co-factors and regulate genes in response to DNA damage and autophagy stimulation, thus leading to accumulation of unresolved DNA damage burden. By combining genomics and functional assays, we describe a molecular mechanism underlying chromatin control of autophagic flux and genotoxic stress surveillance that is broadly applicable to human cell types and can explain HSS establishment.

2021-02-19 | GSE136057 | GEO

Impaired CHD6 function links misregulation of autophagy and DNA damage response to premature ageing [RNA-Seq]

2021-02-19 | GSE135832 | GEO

CHD6 IP from human induced pluripotent stem cells LC-MS-MS

Project description: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.

2021-03-20 | PXD024803 | Pride

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

| S-EPMC8140133 | biostudies-literature

CHD6 transcriptome

Project description:CHD6 transcriptome

| PRJNA432187 | ENA

CHD6 transcriptome

Project description:HEK293T cells were transfected with plasmids expressing a control siRNA or a siRNA especific for CHD6 protein. 48H post-transfection, total RNA was isolated and used for transcriptome analysis. Four biological replicates carried out by triplicate were used.

2018-01-31 | GSE109848 | GEO

Impaired CHD6 function links misregulation of autophagy and DNA damage response to premature ageing

Project description:Impaired CHD6 function links misregulation of autophagy and DNA damage response to premature ageing

| PRJNA675606 | ENA

RNA-seq, ChIP-seq and Mnase-Seq analysis of CHD6-silenced prostate cancer cells C4-2

Project description:Purpose: Study of the role of CHD6 linking nucleosome ejection in castration-resistant prostate cancer(CRPC) Method: The expression of CHD6 or E2F1 was silenced by 2 shRNAs (3 replicates) targeted at CHD6 or E2F1 in C4-2 cells, scramble RNA as control. mRNA profiles and genome-wide chromatin-state maps were generated by deep sequencing. CHD6 and IgG ChIP was conducted in C4-2 cells. MNase before and after CHD6-silenced was conducted in C4-2 cells. Results: E2F1 and E2F1 downstream genes were significantly down regulated by CHD6 knockdown. The binding of CHD6 on chromatin is required for nucleosome eviction in transcriptional activation of oncogenic pathways.

2022-10-18 | GSE214212 | GEO

Impaired CHD6 function links misregulation of autophagy and DNA damage response to premature ageing [RNA-Seq]

Project description:Impaired CHD6 function links misregulation of autophagy and DNA damage response to premature ageing [RNA-Seq]

| PRJNA560229 | ENA