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Defining the interactome of CHD4 in fusion-positive rhabdomyosarcoma

ABSTRACT: The goal of this study was to explore in detail how the chromatin remodeler and NuRD subunit CHD4 controls the oncogenic signature of the tumor driver and fusion protein PAX3-FOXO1 in fusion-positive rhabdomyosarcoma. To this aim, we defined the interactome of CHD4 by LC-MS, identified its location in the genome by ChIP-seq, assessed its influence on DNA accessibility by DNase I hypersensitivity assays, and determined its target genes by RNA-seq.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Alveolar Sac

DISEASE(S): Alveolar Rhabdomyosarcoma

SUBMITTER: Fabian Frommelt

LAB HEAD: Beat W. Schäfer

PROVIDER: PXD015231 | Pride | 2020-08-11

REPOSITORIES: Pride

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			Action	DRS
	20161021_03_WT1E.raw	Raw
	20161021_04_WT1H.raw	Raw
	20161021_05_N1E.raw	Raw
	20161021_06_N1H.raw	Raw
	20161021_07_C1E.raw	Raw

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Publications

NuRD subunit CHD4 regulates super-enhancer accessibility in rhabdomyosarcoma and represents a general tumor dependency.

Marques Joana G JG Gryder Berkley E BE Pavlovic Blaz B Chung Yeonjoo Y Ngo Quy A QA Frommelt Fabian F Gstaiger Matthias M Song Young Y Benischke Katharina K Laubscher Dominik D Wachtel Marco M Khan Javed J Schäfer Beat W BW

eLife 20200803

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 downst ...[more]

PMID: 32744500

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Expression data from glioblastoma cells after ZFHX4 or CHD4 suppression.

Project description:ZFHX4 and CHD4 suppression independently shift tumor initiating cells out of a stem like state and toward a differentiated morphology. After gene suppression via transduction of a lentivirally mediated shRNA construct, RNA was extracted 3 and 5 days later and was hybridized on Affymetrix microarrays. Total RNA was extracted 3 and 5 days after shRNA transduction of 0308 TICs, for 3 (for CHD4) or 5 (ZFHX4) independent experiments. Complementary RNA synthesis and hybridization/scanning of U133 plus 2.0 microarrays using GeneChip products (Affymetrix) was done as described in the GeneChip manual.

2014-01-16 | E-GEOD-52363 | biostudies-arrayexpress

A regulatory role for CHD4 in maintenance of the spermatogonial stem cell pool

Project description:Maintenance and self-renewal of the spermatogonial stem cell (SSC) population is the cornerstone of male fertility. In this manuscript we have identified a key role for the nucleosome remodelling protein Chromodomain Helicase DNA binding protein 4 (CHD4) in regulating SSC function. Gene expression analyses revealed that CHD4 expression is largely restricted to spermatogonia in the mouse testis, and is particularly enriched in SSCs. Using spermatogonial transplantation techniques and RNAi mediated knockdown it was established that loss of Chd4 expression significantly impairs SSC regenerative capacity, resulting in a ~50% reduction in colonisation of recipient testes. A single cell RNA-seq comparison depicted reduced expression of ‘self-renewal’ genes such as Gfra1 and Pten following Chd4 knockdown, along with increased expression of signature progenitor genes, Neurog3 and Dazl. Co-immunoprecipitation analyses demonstrated that CHD4 regulates gene expression in spermatogonia not only though its traditional association with the remodelling complex NuRD, but also via interaction with the GDNF-responsive transcription factor SALL4. Cumulatively, the results of this study depict a previously unappreciated fundamental role for CHD4 in controlling fate decisions in the spermatogonial pool.

2021-06-17 | PXD022066 | Pride

ZFHX4 and CHD4 ChIP sequencing in glioblastoma tumor initiating cells

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

NuRD subunit CHD4 regulates super-enhancer accessibility in Rhabdomyosarcoma and represents a general tumor dependency

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

CHD4 regulates super-enhancer accessibility in fusion-positive rhabdomyosarcoma and is essential for tumor growth

2019-12-20 | GSE140115 | GEO

The modulation of CHD4 nucleosome remodelling activity by auxiliary domains suggests unifies mechanistic aspects of chromatin remodelling across enzyme families

Project description:We determine the impact of auxiliary domains on the nucleosome sliding activity of CHD4. This dataset comprises the crosslinking mass spectrometry data we reported.

2023-03-11 | PXD033633 | Pride

Multiple Overlapping Mammalian Chromatin Remodeling Systems Collaborate Genome-wide at Dynamic Chromatin Transitions (ChIP-Seq)

Project description:ATP-dependent chromatin remodeling is an essential process required for the dynamic organization of chromatin structure. Here we describe the genome-wide location and activity of three remodeler proteins with diverse physiological functions in the mouse genome: Brg1, Chd4, and Snf2h. The localization patterns of all three proteins significantly overlap with one another and with regions of accessible chromatin. Furthermore, using inducible mutant variants, we demonstrate that the catalytic activity of these proteins contributes to the remodeling of chromatin genome-wide, and that each of these remodelers can independently regulate chromatin reorganization at distinct sites. Most regions require the activity of more than one remodeler to regulate accessibility. These findings provide a dynamic view of chromatin organization, and highlight the differential contributions of remodelers to chromatin maintenance in higher eukaryotes. We examine the genome-wide location and activity of three remodeler proteins (Brg1, CHD4 and Snf2h)

2013-12-24 | E-GEOD-53583 | biostudies-arrayexpress

Multiple Overlapping Mammalian Chromatin Remodeling Systems Collaborate Genome-wide at Dynamic Chromatin Transitions (Dnase-Seq)

2013-12-24 | E-GEOD-53584 | biostudies-arrayexpress

The HP1 protein interactome of mouse embryonic stem cells

Project description:The family of Heterochromatin Protein 1 (HP1) consists of highly conserved proteins, which have important functions in the nucleus of eukaryotic cells. In mammals there are three HP1 paralogs: HP1(alpha), Hp1(beta), and Hp1(gamma)They are encoded by the Cbx5, Cbx1, and Cbx3 genes, respectively. Hp1 and Hp1 stably interact with Chd4 and Adnp to form the ChAHP complex. In this project, Chd4, Adnp, and the three Cbx genes were endogenously tagged with a FLAG-Avi tag in mouse embryonic stem cells. The tagged proteins were subjected to tandem-affinity purification and analysis by mass spectrometry.

2018-05-22 | PXD006226 | Pride

BioID HEK293T PAX3-FOXO1 proximity labelling

Project description:PAX3-FOXO1 is a fusion transcription factor that is the main driver of tumorigenesis leading to the development of alveolar rhabdomyosarcoma (aRMS). Since aRMS cells are addicted to PAX3-FOXO1 activity, the fusion protein also represents a major target for therapeutic interference, which is however challenging as transcription factors usually cannot be inhibited directly by small molecules. Hence, characterization of the biology of PAX3-FOXO1 might lead to the discovery of new possibilities for an indirect inhibition of its activity. Here, our goal was to characterize the proteomic neighborhood of PAX3-FOXO1 and to find candidates potentially affecting its activity and tumor cell viability. Towards this aim, we expressed BirA fused versions of PAX3-FOXO1 (N- and C-terminal) in HEK293T cells under presence of biotin. In the control setup, we expressed the BirA enzyme alone. After Streptavidin purification of biotinylated proteins, we performed mass spectrometry and quantified relative abundances compared to control conditions. This enabled us to determine PAX3-FOXO1 proximal proteins, which we investigated further in orthogonal endogenous systems.

2021-09-16 | PXD022187 | Pride

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