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

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

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Jason Low

LAB HEAD: Joel Mackay

PROVIDER: PXD033633 | Pride | 2023-03-11

REPOSITORIES: Pride

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	20201218_QEHFX3_JLow_JZ_XLMS_C1.raw	Raw
	20201218_QEHFX3_JLow_JZ_XLMS_C1_reinject.raw	Raw
	20201218_QEHFX3_JLow_JZ_XLMS_C2.raw	Raw
	20201218_QEHFX3_JLow_JZ_XLMS_C3.raw	Raw
	20201222_CHD4only_BS3_PLINK_SEARCH.zip	Other

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Publications

The role of auxiliary domains in modulating CHD4 activity suggests mechanistic commonality between enzyme families.

Zhong Yichen Y Moghaddas Sani Hakimeh H Paudel Bishnu P BP Low Jason K K JKK Silva Ana P G APG Mueller Stefan S Deshpande Chandrika C Panjikar Santosh S Reid Xavier J XJ Bedward Max J MJ van Oijen Antoine M AM Mackay Joel P JP

Nature communications 20221206 1

CHD4 is an essential, widely conserved ATP-dependent translocase that is also a broad tumour dependency. In common with other SF2-family chromatin remodelling enzymes, it alters chromatin accessibility by repositioning histone octamers. Besides the helicase and adjacent tandem chromodomains and PHD domains, CHD4 features 1000 residues of N- and C-terminal sequence with unknown structure and function. We demonstrate that these regions regulate CHD4 activity through different mechanisms. An N-term ...[more]

PMID: 36473839

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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

Defining the interactome of CHD4 in fusion-positive rhabdomyosarcoma

Project description: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.

2020-08-11 | PXD015231 | Pride

The NuRD chromatin remodelling complex regulates brain cortical development

Project description:Dynamic changes of histone epigenetic modifications and chromatin structure represent an universal mechanism by which cells adapt their transcriptional response to rapidly changing environmental conditions. During neuronal development, extensive chromatin remodeling takes place allowing the transition of pluripotent cells into differentiated neurons. Here we report that the ATP-dependent chromatin remodeling complex NuRD, which couples ATP-dependent nucleosome sliding with histone deacetylase activity, is a major remodeling complex in embryonic brain and plays an instructive role during mouse neuronal development. Importantly, the ATPase subunits of NuRD complex CHD3, CHD4 and CHD5 undergo a functional switch, thereby regulating distinct aspects of neuronal differentiation and migration in a sequential and mostly non-overlapping manner. We conclude that the recruitment of NuRD complexes containing specific CHDs to gene promoters and enhancers plays an instructive role in brain development. Gene expression analysis was performed in the mouse embryonic cortex at three developmental stages: E12.5, E15.5 and E18.5 using total RNA obtained from four embryos for each time point.

2015-06-27 | E-GEOD-70298 | biostudies-arrayexpress

Comprehensive cross-linking mass spectrometry reveals molecular insights into the between peripheral and core NuRD complex subunits

Project description:Affinity purifications of CHD4 and CDK2AP2 to identify their interactors. The C-terminally tagged CHD4 has a C-terminal truncation to test whether this domain is required for the interaction with other NuRD subunits. GFP-purifications of both N- and C-terminally tagged CDK2AP2 were performed.

2020-12-07 | PXD017378 | Pride

Chd4 deficiency effect on mouse embryonic stem cells

Project description:Our study reveal that Chd4 is essential for stemness maintenance of ESCs. As Chd4 deficient ESCs show attentuated self-renewal ability and induced differentiation marker gene expression. To confirm the effect of Chd4 on the transcriptome profile of ESCs, we performed microarray analyses for Chd4 deficient ESCs.

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Chd4 controls Ripk3 dependent necroptosis during muscle regeneration

Project description:We performed a label-free LC-MS/MS study to analyse the role of Chd4 regulation in MuSC in suppressing genes enabling programmed cell death as part of the muscle regeneration program. Lox-cre recombination was used to create a deletion mutant of the CHD4 chromatin modifier (exons 12-21). A pseudo "infection" with GFP was used as control. Proteomics analysis here serves as a method to compare the differentially deregulated proteins upon knockdown of Chd4 in MuSCs using Adenoviral CRE recombination.

2020-04-02 | PXD010370 | Pride

Transcriptome of E18.5 CHD4-M195I mouse hearts

Project description:Purpose: The goal of this study is to compare the cardiac transcriptome profiling (RNA-seq) of WT and CHD4-M195I hearts at E18.5 to conclude genes affected by this CHD4 mutation. Methods: mRNA profiles of E18.5 WT and CHD4-M195I mouse hearts were generated by deep sequencing, n=4 for each genotype, using Illumina HiSeq2500. The sequence reads that passed quality filters were analyzed at the transcript isoform level with two methods: Burrows–Wheeler Aligner (BWA) followed by ANOVA (ANOVA) and TopHat followed by Cufflinks. Results: RNA-sequencing (RNA-seq) analyses on E18.5 WT and CHD4-M195I hearts and identified 323 genes that were differentially expressed [adjusted P value <0.05, |log2(Fold Change)| > 0.5], 113 upregulated and 210 downregulated in CHD4-M195I hearts.

2023-05-08 | GSE229050 | GEO

Identification and characterization of novel proteins associated with CHD4

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