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GFI1 tethers the NuRD complex to open and transcriptionally active chromatin in myeloid progenitors

ABSTRACT: GFI is a DNA binding transcriptional repressor that regulates myeloid differentiation. Here, we show that GFI1 interacts with the chromodomain helicase CHD4 and other components of the nucleosome remodeling and deacetylase (NuRD) complex. Our data demonstrated that GFI1 and GFI1/CHD4 complexes occupy sites of open chromatin enriched for histone marks associated with active transcription or different sets of genes that are either enriched for IRF1 or SPI-1 consensus binding sites. In addition, our study provided evidence that GFI1 affects the chromatin remodeling activity of the NuRD complex. Overall, our results indicate that GFI1/CHD4 complexes control chromatin openness and histone modifications differentially to regulate target genes, which govern the immune response, nucleosome organization, or metabolic processes.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

SUBMITTER: Halil Bagci

LAB HEAD: Tarik Moroy

PROVIDER: PXD028945 | Pride | 2021-11-02

REPOSITORIES: Pride

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GFI1 tethers the nucleosome-remodeling and histone-deacetylase (NuRD) complex to open and transcriptionally active chromatin in myeloid progenitors

Project description:Purpose: The goals of this study are to identify sites in genomic DNA that are occupied by GFI1 and the NurD complex, represented by its member the chromodomain helicase CHD4 or by a complex of GFI1 and CHD4 in myeloid precursors cells and to determined the effect on gene expression. Methods: Granulocytic-monocytic precursors (GMPs) as well as pre neutrophils and mature neutrophils were sorted by flow cytometry from murine bone marrow and sujected to RNA-seq and Chromatin-immuno-precipitation and sequencing (ChIP-Seq) and ATAC-seq procedures. Ch-IP seq experiments were done with antibodies against GFI1, CHD4 or different histone H3 modifications as indicated. Results: GFI1 and GFI1/CHD4 complexes occupies both promoter and enhancers of genes that are down or upregulated during the formation of preNeu and matNeu cells from GMPs Conclusions: Myeloid precursors required GFI1 to tether the NuRD complex to a specific set of target genes that are either transcriptionally active or poised to enable their transcriptional regulation during neutrophil differentiation by chromatin remodeling

2021-10-13 | GSE173533 | GEO

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

ChIP-seq of NuRD components and pluripotency factors in wild-type, Mbd3 and Sall4/1 mutant embryonic stem cells

Project description:Members of the Nucleosome Remodeling and Deacetylase (NuRD) complex Mbd3 and Mi2beta (Chd4) along with pluripotency regulators Nanog, Oct4, Klf4 and Esrrb were profiled for chromatin association by ChIP-seq in mouse embryonic stem cells mutant for Mbd3, Sall4 and/or the related Sall1 pluripotency-associated factors.

2016-08-09 | E-MTAB-4565 | 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

Effects of MBD3 depletion on nucleosome occupancy in MCF-7 cells

Project description:We and others have identified that MBD3/NuRD localizes at active promoters and enhancers, suggesting an active role of NuRD at open chromatin region. Because NuRD includes nucleosome remodelers, CHD3 and CHD4, we hypothesized that NuRD regulates nucleosome organization at open chromatin region. To test this idea, we performed micrococcal nuclease digestion followed by massively parallel sequencing (MNase-seq) in MBD3 knockdowned MCF-7 cells. We observed the decrease of nucleosome occupancy at promoters and enhancers in MBD3 knockdowned cells. Our results suggest a regulatory role of MBD3/NuRD at open chromatin region. Mapped nucleosome positioning in control (shLuc) and MBD3 knockdowned MCF-7 cells, in duplicate.

2013-10-31 | E-GEOD-51097 | 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

Unique Protein Interaction Networks Define The Chromatin Remodeling Module of The NuRD Complex

Project description:The combination of four proteins and their paralogues including MBD2/3, GATAD2A/B, CDK2AP1, and CHD3/4/5, which we refer to as the MGCC module, form the chromatin remodeling module of the Nucleosome Remodeling and Deacetylase (NuRD) complex. To date, mechanisms by which the MGCC module acquires paralogue-specific function and specificity have not been addressed. Understanding the protein-protein interaction (PPI) network of the MGCC subunits is essential in defining underlying mechanisms of gene regulation. Therefore, using pulldown followed by mass spectrometry analysis (PD-MS) we report a proteome-wide interaction network of the MGCC module in a paralogue-specific manner. Our data also demonstrate that the disordered C-terminal region of CHD3/4/5 is a gateway to incorporate remodeling activity into both the ChAHP (CHD4, ADNP, HP1γ) and NuRD complexes in a mutually exclusive manner. We define a short aggregation prone region (APR) within the C-terminal segment of GATAD2B that is essential for the interaction of CHD4 and CDK2AP1 with the NuRD complex. Finally, we also report an association of CDK2AP1 with the Nuclear Receptor Co-Repressor (NCOR) complex. Overall, this study provides insight into the possible mechanisms through which the MGCC module can achieve specificity and diverse biological functions.

2023-03-11 | PXD025263 | Pride

The nucleosome remodeling and deacetylase complex protein CHD4 regulates neural differentiation of mouse embryonic stem cells by down-regulating p53

Project description:Lineage specification of the three germ layers occurs during early embryogenesis and is critical for normal development. The nucleosome remodeling and deacetylase (NuRD) complex is a repressive chromatin modifier that plays a role in lineage commitment. However, the role of chromodomain helicase DNA-binding protein 4 (CHD4), one of the core subunits of the NuRD complex, in neural lineage commitment is poorly understood. Here, we report that the CHD4/NuRD complex plays a critical role in neural differentiation of mouse embryonic stem cells (ESCs). We found that RNAi-mediated Chd4 knockdown suppresses neural differentiation, as did knockdown of methyl-CpG binding domain protein Mbd3, another NuRD subunit. Chd4 and Mbd3 knockdowns similarly affected changes in global gene expression during neural differentiation and up-regulated several mesendodermal genes. However, inhibition of mesendodermal genes by knocking out the master regulators of mesendodemal lineages, Brachyury and Eomes, through a CRISPR/Cas9 approach could not restore the impaired neural differentiation caused by the Chd4 knockdown, suggesting that CHD4 controls neural differentiation not by repressing other lineage differentiation processes. Notably, Chd4 knockdown increased the acetylation levels of p53, resulted in increased protein levels of p53. Double knockdown of Chd4 and p53 restored the neural differentiation rate. Furthermore, overexpression of BCL2, a downstream factor of p53, partially rescued the impaired neural differentiation caused by the Chd4 knockdown. Our findings reveal that the CHD4/NuRD complex regulates neural differentiation of ESCs by down-regulating p53.

2018-11-07 | GSE114389 | GEO

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