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Chd1 regulates repair of promoter-proximal DNA breaks to sustain hypertranscription in embryonic stem cells

ABSTRACT: Chd1 regulates repair of promoter-proximal DNA breaks to sustain hypertranscription in embryonic stem cells

PROVIDER: PRJNA546008 | ENA |

REPOSITORIES: ENA

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Chd1 regulates repair of promoter-proximal DNA breaks to sustain hypertranscription in embryonic stem cells

Project description:Stem and progenitor cells undergo a global elevation of nascent transcription, or hypertranscription, during key developmental transitions involving rapid cell proliferation. The chromatin remodeler Chd1 binds to RNA Pol I and II genes and is required for hypertranscription in embryonic stem (ES) cells in vitro and the early post-implantation epiblast in vivo. Biochemically, Chd1 has been shown to facilitate transcription at least in part by removing nucleosomal barriers to elongation, but its mechanism of action in stem cells remains poorly understood. Here we report a novel role for Chd1 in the repair of promoter-proximal endogenous double-stranded DNA breaks (DSBs) in ES cells. An unbiased proteomics approach revealed that Chd1 interacts with several DNA repair factors including ATM, Parp1, Kap1 and Topoisomerase 2. We show that wild-type ES cells display high levels of phosphorylated H2AX and Kap1 at chromatin, notably at rDNA in the nucleolus, in a Chd1-dependent manner. Loss of Chd1 leads to an extensive accumulation of DSBs at Chd1 target Pol II genes and rDNA. Genes prone to DNA breaks in Chd1-null ES cells tend to be longer genes with GC-rich promoters, a more labile nucleosomal structure and roles in chromatin organization, transcription and signaling. These results reveal a vulnerability of hypertranscribing stem cells to endogenous DNA breaks, with important implications for developmental and cancer biology.

2021-06-14 | PXD024604 | Pride

Chd1 regulates repair of promoter-proximal DNA breaks to sustain hypertranscription in embryonic stem cells

Project description:Stem and progenitor cells undergo a global elevation of nascent transcription, or hypertranscription, during key developmental transitions involving rapid cell proliferation. The chromatin remodeler Chd1 binds to genes transcribed by RNA Pol I and II and is required for hypertranscription in embryonic stem (ES) cells in vitro and the early post-implantation epiblast in vivo. Biochemically, Chd1 has been shown to facilitate transcription at least in part by removing nucleosomal barriers to elongation, but its mechanism of action in stem cells remains poorly understood. Here we report a novel role for Chd1 in the repair of promoter-proximal endogenous double-stranded DNA breaks (DSBs) in ES cells. An unbiased proteomics approach revealed that Chd1 interacts with several DNA repair factors including ATM, Parp1, Kap1 and Topoisomerase 2β. We show that wild-type ES cells display high levels of phosphorylated H2AX and Kap1 at chromatin, notably at rDNA in the nucleolus, in a Chd1-dependent manner. Loss of Chd1 leads to an extensive accumulation of DSBs at Chd1-bound Pol II-transcribed genes and rDNA. Genes prone to DNA breaks in Chd1-null ES cells tend to be longer genes with GC-rich promoters, a more labile nucleosomal structure and roles in chromatin organization, transcription and signaling. These results reveal a vulnerability of hypertranscribing stem cells to endogenous DNA breaks, with important implications for developmental and cancer biology.

2021-06-10 | GSE132137 | GEO

Chd1 protects genome integrity at promoters to sustain hypertranscription in embryonic stem cells.

Project description: Not available

| S-EPMC8357957 | biostudies-literature

Chd1 is essential for the high transcriptional output and rapid growth of the mouse epiblast

Project description:The pluripotent mammalian epiblast undergoes unusually fast cell proliferation. This rapid growth is expected to generate a high transcriptional demand, but the underlying mechanisms remain unknown. We report that the chromatin remodeler Chd1, which binds the activating histone mark H3K4me3 and is associated with transcription, is required for development of the mouse epiblast. Chd1-/- embryos exhibit proliferation defects and increased apoptosis, are smaller than controls by E5.5, and fail to grow, become patterned or gastrulate. We show that Chd1-/- ES cells have a self-renewal defect and a genome-wide reduction in transcriptional output that is associated with losses in RNA Pol II elongation at growth-promoting genes, including ribosomal proteins. We also report that Chd1 directly regulates ribosomal RNA transcription and that both Chd1-/- epiblast cells in vivo and ES cells in vitro express significantly lower levels of ribosomal RNA. Single cell analyses reveal abnormal nucleolar morphology in mutants in vivo and in vitro. These data indicate that Chd1 promotes a globally elevated transcriptional output required to sustain the distinct rapid growth of the mouse epiblast.

2014-12-31 | GSE57609 | GEO

Histone exchange in wildtype, isw1, chd1, isw1 chd1 and ioc4 yeast strains

Project description:Histone exchange in wildtype, isw1, chd1, isw1 chd1 and ioc4 yeast strains.

2012-07-25 | GSE32043 | GEO

Microarray of CHD1 Knockdown in PC3 cells and CHD1 knockout in LNCaP cells

Project description:We used microarrays to study the global gene expression and identified differentially expressed genes in CHD1 knockdown PC-3 cells and CHD1 KO LNCaP cells, aiming to identify genes and pathways that are regulated by CHD1

2017-02-10 | GSE84970 | GEO

Histone exchange in wildtype, isw1, chd1, isw1 chd1 and ioc4 yeast strains

Project description:Histone exchange in wildtype, isw1, chd1, isw1 chd1 and ioc4 yeast strains. Two color experiment. Deletion mutant vs. WT cells. Biological replicates=3 per IP per cell type.

2012-07-24 | E-GEOD-32043 | biostudies-arrayexpress

Isw1 and Chd1 maintain chromatin organization during transcription [isw1 chd1 mutant expression]

Project description:Gene expression microarray experiments to determine the existence of intragenic (cryptic) transcripts in an isw1 chd1 mutant yeast strain.

2012-07-25 | GSE37158 | GEO

Expression data from Chd1-deficient mouse ES cells (E14 cell lines) and genome-wide binding of Chd1 in parental ES cells

Project description:We used microarrays to study the effect of Chd1 loss of function in mouse ES cells. We used ChIP-chip to analyze genome-wide binding of Chd1 in normal ES cells. Mouse Embryonic Stem (ES) cells were infected with a lentiviral vector (pSicoR-mCherry) for expression of a shRNA against Chd1 and GFP (as a control). mCherry-sorted ES cells were plated and individual clones were selected and grown under normal ES cell conditions. 6 ES cell clonal lines were isolated and analyzed along with the parental E14 cell line. The final analysis consisted in 3 control cell lines (E14, E1 and G8) and 4 Chd1-deficient cells (3 different clones using a shRNA sequence #1- C1i5, C1i6 and C1i9; 1 clone using a different shRNA (#4) sequence targeting Chd1- C4i2). RNA samples were isolated from these Chd1-deficient ES cells and control ES cells, and hybridized on Affymetrix chip. For ChIP-chip, parental E14 ES cell line was used.

2009-08-13 | E-GEOD-16462 | biostudies-arrayexpress

Absolute Scaling of Single-Cell Transcriptomes Reveals Pervasive Hypertranscription in Adult Stem and Progenitor Cells

Project description:Hypertranscription facilitates biosynthetically demanding cellular state transitions through global upregulation of the nascent transcriptome. Despite its potential widespread relevance, documented examples of hypertranscription remain few and limited predominantly to early development. This limitation is in large part due to the fact that modern sequencing approaches, including single-cell RNA sequencing (scRNA-seq), generally assume similar levels of transcriptional output per cell. Here, we use molecule counting and spike-in normalization to develop absolute scaling of single-cell RNA sequencing data. Absolute scaling enables an estimation of total transcript abundances per cell, which we validate in embryonic stem cell (ESC) and germline data and apply to adult mouse organs at steady-state or during regeneration.

2022-12-21 | GSE221184 | GEO

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