NuRD subunit CHD4 regulates super-enhancer accessibility in Rhabdomyosarcoma and represents a general tumor dependency
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA655884 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12411109.fastq.gz | Fastqsanger.gz | |||
| SRR12411110.fastq.gz | Fastqsanger.gz | |||
| SRR12411111.fastq.gz | Fastqsanger.gz | |||
| SRR12411112.fastq.gz | Fastqsanger.gz | |||
| SRR12411113.fastq.gz | Fastqsanger.gz |
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Project description:ATP-dependent chromatin remodelers modulate gene expression by regulating genome accessibility and can contribute to tumorigenesis. In fusion-positive rhabdomyosarcoma (FP-RMS), we have previously identified the chromatin remodeler and NuRD subunit CHD4 as an essential gene for tumor survival. Here, we demonstrate that the FP-RMS vulnerability to CHD4 goes beyond its function as a NuRD member. Mechanistically, CHD4 interacts with BRD4 and co-localizes with the tumor driver and fusion protein PAX3-FOXO1 at super-enhancers where it generates a chromatin architecture permissive for the binding of the fusion protein. This allows the positioning of RNA polymerase 2 at promoters and the expression of the oncogenic program of PAX3-FOXO1. Additionally, analysis of genome-wide cancer dependency databases identifies CHD4 amongst the NuRD subunits as general novel cancer vulnerability. Our findings describe, for the first time, CHD4 as a regulator of super-enhancer-mediated gene expression and establish this chromatin remodeler as an unexpected broad tumor susceptibility.
2020-08-08 | GSE155861 | GEO
Project description:The NuRD complex subunit CHD4 is essential for fusion-positive rhabdomyosarcoma (FP-RMS) survival, but the mechanisms underlying this dependency are not understood. Here, a NuRD-specific CRISPR screen demonstrates that FP-RMS is particularly sensitive to CHD4 amongst the NuRD members. Mechanistically, NuRD complex containing CHD4 localizes to super-enhancers where CHD4 generates a chromatin architecture permissive for the binding of the tumor driver and fusion protein PAX3-FOXO1, allowing downstream transcription of its oncogenic program. Moreover, CHD4 depletion removes HDAC2 from the chromatin, leading to an increase and spread of histone acetylation, and prevents the positioning of RNA Polymerase 2 at promoters impeding transcription initiation. Strikingly, analysis of genome-wide cancer dependency databases identifies CHD4 as a general cancer vulnerability. Our findings describe CHD4, a classically defined repressor, as positive regulator of transcription and super-enhancer accessibility as well as establish this remodeler as an unexpected broad tumor susceptibility and promising drug target for cancer therapy.
| S-EPMC7438112 | biostudies-literature
Project description:ATP-dependent chromatin remodelers modulate gene expression by regulating genome accessibility and can contribute to tumorigenesis. In fusion-positive rhabdomyosarcoma (FP-RMS), we have previously identified the chromatin remodeler and NuRD subunit CHD4 as an essential gene for tumor survival. Here, we demonstrate that the FP-RMS vulnerability to CHD4 goes beyond its function as a NuRD member. Mechanistically, CHD4 interacts with BRD4 and co-localizes with the tumor driver and fusion protein PAX3-FOXO1 at super-enhancers where it generates a chromatin architecture permissive for the binding of the fusion protein. This allows the positioning of RNA polymerase 2 at promoters and the expression of the oncogenic program of PAX3-FOXO1. Additionally, analysis of genome-wide cancer dependency databases identifies CHD4 amongst the NuRD subunits as general novel cancer vulnerability. Our findings describe, for the first time, CHD4 as a regulator of super-enhancer-mediated gene expression and establish this chromatin remodeler as an unexpected broad tumor susceptibility.
2019-12-20 | GSE140115 | GEO
Project description:We established Ewing sarcoma cells (SKNMC) stably expressing two doxycycline-inducible shRNAs targeting the NuRD component CHD4 to study its influence on DNA accessibility.
2023-11-07 | GSE224002 | GEO
Project description:Cardiac development relies on proper cardiomyocyte differentiation including expression and assembly of cell-type specific actomyosin subunits into a functional cardiac sarcomere. Control of this process involves not only promoting expression of cardiac sarcomere subunits but also repressing expression of non-cardiac myofibril paralogs. This level of transcriptional control requires broadly expressed multiprotein machines that modify and remodel the chromatin landscape to restrict transcription machinery access. Prominent among these is the Nucleosome Remodeling and Deacetylase (NuRD) complex, which includes the catalytic core subunit CHD4. Here, we demonstrate that direct CHD4-mediated repression of skeletal and smooth muscle myofibril isoforms is required for normal cardiac sarcomere formation, function, and embryonic survival early in gestation. Through transcriptomic and system genome-wide analyses of CHD4 localization, we identified novel CHD4 binding sites in smooth muscle myosin heavy chain, fast skeletal α-actin, and the fast skeletal troponin complex genes. We further demonstrate that in the absence of CHD4, cardiomyocytes in the developing heart form a hybrid muscle cell that contains cardiac, skeletal and smooth muscle myofibril components. These misexpressed paralogs intercalate into the nascent cardiac sarcomere to disrupt sarcomere formation and cause impaired cardiac function in utero. These results demonstrate the genomic and physiological requirements for CHD4 in mammalian cardiac development.
2018-05-15 | GSE109012 | GEO
Project description:Glioblastomas (GBM) harbor subpopulations of therapy-resistant tumor initiating cells (TICs) that are self-renewing and multipotent. To understand the regulation of the TIC state, we performed an image-based screen for genes regulating GBM TIC maintenance and identified ZFHX4, a 397-kDa transcription factor. ZFHX4 is required to maintain TIC-associated phenotypes in vitro, suggesting that ZFHX4 regulates TIC differentiation, and its suppression increases glioma-free survival in intracranial xenografts. ZFHX4 interacts with CHD4, a core member of the NuRD (nucleosome remodeling and deacetylase) complex. ZFHX4 and CHD4 bind to overlapping sets of genomic loci and control similar gene expression programs. Using expression data derived from GBM patients, we demonstrate ZFHX4 is a master regulator of CHD4-mediated gene expression. These observations define ZFHX4 as a regulatory factor that links the chromatin remodeling NuRD complex and the GBM TIC state. Examination of binding of ZFHX4 and CHD4 across the human genome, using the 0308 tumor initiating cell line. Two replicates for each protein, compared to whole cell extract inputs.
2014-01-16 | E-GEOD-52419 | biostudies-arrayexpress
Project description:Metazoan transcription factors typically regulate large numbers of genes. Here we identify via a CRISPR-Cas9 genetic screen ZNF410, a pentadactyl DNA binding protein that in human erythroid cells directly and measurably activates only one gene, the NuRD component CHD4. Specificity is conveyed by two highly evolutionarily conserved clusters of ZNF410 binding sites near the CHD4 gene with no counterparts elsewhere in the genome. Loss of ZNF410 in adult type human erythroid cell culture systems and xenotransplant settings diminishes CHD4 levels and derepresses the fetal hemoglobin genes. While previously known to be silenced by CHD4, the fetal globin genes are exposed here as among the most sensitive to reduced CHD4 levels. In vitro DNA binding assays and crystallographic studies reveal the ZNF410-DNA binding mode. ZNF410 is a remarkably selective transcriptional activator in erythroid cells whose perturbation might offer new therapeutic opportunities in the treatment of hemoglobinopathies.
2020-12-09 | GSE154960 | GEO
Project description:Metazoan transcription factors typically regulate large numbers of genes. Here we identify via a CRISPR-Cas9 genetic screen ZNF410, a pentadactyl DNA binding protein that in human erythroid cells directly and measurably activates only one gene, the NuRD component CHD4. Specificity is conveyed by two highly evolutionarily conserved clusters of ZNF410 binding sites near the CHD4 gene with no counterparts elsewhere in the genome. Loss of ZNF410 in adult type human erythroid cell culture systems and xenotransplant settings diminishes CHD4 levels and derepresses the fetal hemoglobin genes. While previously known to be silenced by CHD4, the fetal globin genes are exposed here as among the most sensitive to reduced CHD4 levels. In vitro DNA binding assays and crystallographic studies reveal the ZNF410-DNA binding mode. ZNF410 is a remarkably selective transcriptional activator in erythroid cells whose perturbation might offer new therapeutic opportunities in the treatment of hemoglobinopathies.
2020-12-09 | GSE154961 | GEO
Project description:The Nuclesome Remodelling and Deacetylation (NuRD) complex is an epigenetic regulator of gene expression comprising two mutually exclusive ATPase subunits CHD3 or CHD4. Here we show that CHD4 silencing in multiple types of cancer cells de-represses expression of the PADI1 (Protein Arginine Deiminase 1) and PADI3 enzymes that convert arginine to citrulline. Increased PADI1 and PADI3 expression enhances citrullination of three arginines of the key glycolytic regulatory enzyme PKM2 (pyruvate kinase) promoting excessive glycolysis, lowered ATP levels and slowed proliferation. PKM2 citrullination lowers its sensitivity to the allosteric inhibitors Tryptophan and Phenylalanine shifting equilibrium towards the allosteric activator Serine, thereby bypassing the normal physiological regulation of glycolysis by low Serine levels. Our results describe a novel pathway linking epigenetic regulation of PADI1 and PAD3 expression by CHD4 to glycolytic flux and the control of cancer cell growth.
2019-11-03 | GSE134849 | GEO
Project description:The Nuclesome Remodelling and Deacetylation (NuRD) complex is an epigenetic regulator of gene expression comprising two mutually exclusive ATPase subunits CHD3 or CHD4. Here we show that CHD4 silencing in multiple types of cancer cells de-represses expression of the PADI1 (Protein Arginine Deiminase 1) and PADI3 enzymes that convert arginine to citrulline. Increased PADI1 and PADI3 expression enhances citrullination of three arginines of the key glycolytic regulatory enzyme PKM2 (pyruvate kinase) promoting excessive glycolysis, lowered ATP levels and slowed proliferation. PKM2 citrullination lowers its sensitivity to the allosteric inhibitors Tryptophan and Phenylalanine shifting equilibrium towards the allosteric activator Serine, thereby bypassing the normal physiological regulation of glycolysis by low Serine levels. Our results describe a novel pathway linking epigenetic regulation of PADI1 and PAD3 expression by CHD4 to glycolytic flux and the control of cancer cell growth.
2019-11-03 | GSE134848 | GEO