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Chd4 controls Ripk3 dependent necroptosis during muscle regeneration

ABSTRACT: 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.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Muscle Stem Cell

SUBMITTER: Carsten Kuenne

LAB HEAD: Marcus Krüger

PROVIDER: PXD010370 | Pride | 2020-04-02

REPOSITORIES: Pride

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Attenuated Epigenetic Suppression of Muscle Stem Cell Necroptosis Is Required for Efficient Regeneration of Dystrophic Muscles.

Sreenivasan Krishnamoorthy K Ianni Alessandro A Künne Carsten C Strilic Boris B Günther Stefan S Perdiguero Eusebio E Krüger Marcus M Spuler Simone S Offermanns Stefan S Gómez-Del Arco Pablo P Redondo Juan Miguel JM Munoz-Canoves Pura P Kim Johnny J Braun Thomas T

Cell reports 20200501 7

Somatic stem cells expand massively during tissue regeneration, which might require control of cell fitness, allowing elimination of non-competitive, potentially harmful cells. How or if such cells are removed to restore organ function is not fully understood. Here, we show that a substantial fraction of muscle stem cells (MuSCs) undergo necroptosis because of epigenetic rewiring during chronic skeletal muscle regeneration, which is required for efficient regeneration of dystrophic muscles. Inhi ...[more]

PMID: 32433961

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Distinct requirements of CHD4 during B cell development and antibody response

Project description:Immunoglobulin heavy chain (Igh) class switch recombination (CSR) requires B cell proliferation, germline transcription, AID-instigated generation of DNA double strand breaks and DNA end-joining. How these various DNA-protein interactions and DNA transactions at Igh occur within the context of the chromatin landscape are largely unknown. Histone post-translational modifications can modulate chromatin accessibility and one such epigenetic mark, H3K9me3 is present at activated Igh switch sequences that serve as recombination targets during CSR. The chromatin remodeling protein CHD4 binds H3K9me3 and shapes chromatin accessibility and gene expression in various cell types, but its role in B cell biology is yet to be elucidated. Here, we conditionally ablated CHD4 expression in different stages of B cell development. We find that while CHD4 is essential for early B cell development, it is dispensable for homeostatic maintenance of mature naïve B cells and differentiation into antigen-specific early memory B cells and plasmablasts. However, loss of CHD4 in activated B cells leads to a severe defect in CSR, accompanied by markedly impaired cellular proliferation. Conditional deletion of p53 rescued the proliferation defect but failed to restore CSR due to a failure of AID to be efficiently recruited to Igh. This work unmasks a context-dependent role of CHD4 in B cell development and identifies CHD4 as a novel effector of CSR that influences B cell proliferation and recruitment of AID to Igh.

2019-05-29 | GSE128321 | GEO

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

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.

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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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Identification and characterization of novel proteins associated with CHD4

Project description:CHD (chromodomain helicase DNA binding protein) family is composed of nine members of chromatin remodeling factors that regulate chromatin structure in an ATP-dependent manner. Among them, CHD4 contributes to many basic cellular functions during development mainly through multiple proteins interacting with CHD4 including NuRD (nucleosome remodeling and deacetylase activities) complex, which contains histone deacetylase HDAC1/2. However, functions of CHD4 that are not mediated by NuRD complexes have also been found, implying the existence of unknown proteins that are associated with CHD4. In the present study, we generated CHD4 FLAG-tag knock-in cells in HeLa-S3 and HEK293T cells and sought proteins bound to CHD4 with the use of immunoprecipitation and liquid chromatography and tandem MS (LC-MS/MS) analysis. We found that LCORL (ligand dependent nuclear receptor corepressor like) and NOL4L (nucleolar protein 4 like) were reproducibly identified as a novel CHD4 interactors. RNA-sequencing analysis of HEK293T cells depleted of CHD4, LCORL, and NOL4L revealed consistent upregulation of genes related to the Notch pathway. Our results thus suggest that both NOL4L and LCORL may cooperate with CHD4 to suppress the Notch pathway in mammalian cells.

2022-01-01 | GSE190369 | GEO

beta 1 integrin signaling governs necroptosis via the chromatin remodeling factor CHD4

Project description:Fibrosis, characterized by sustained activation of myofibroblasts and excessive extracellular matrix (ECM) deposition, is known to be associated with chronic inflammation. RIPK3, a key kinase mediating TNF-driven necroptosis signaling, is upregulated in fibrosis and contributes to the TNF-mediated inflammation. In bile duct ligation-induced liver fibrosis, we found that myofibroblasts are the major cell type expressing RIPK3. Genetic ablation of beta1 integrins, the major profibrotic ECM receptors in fibroblasts, not only abolished ECM fibrillogenesis but also blunted RIPK3 expression via an epigenetic mechanism mediated by the chromatin remodeling factor CHD4. While the function of CHD4 has been conventionally linked to NuRD and ChAHP complexes, we found that CHD4 potently repressed a set of genes, including Ripk3, with high locus specificity but independent of either the NuRD or ChAHP complex. Thus, our data uncover that beta1 integrin intrinsically links fibrotic signaling to RIPK3-driven inflammation via a novel mode of action of CHD4.

2023-10-30 | PXD041505 | Pride

Attenuated epigenetic suppression of muscle stem cell necroptosis is required for efficient regeneration of dystrophic muscle [RNA-seq 1]

Project description:We performed a thorough study to analyze the epigenetic suppression of genes enabling programmed cell death as part of the muscle regeneration program. RNAseq analysis here serves as a method to compare the differentially deregulated genes upon knockdown of Chd4 in MuSCs using Adenoviral CRE recombination.

2020-04-02 | GSE117008 | GEO

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

Defining the interactome of CHD4 in fusion-positive rhabdomyosarcoma

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2020-08-11 | PXD015231 | Pride

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