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Physical and functional interactions between the histone H3K4 demethylase JARID1A and the NuRD complex

ABSTRACT: Histone H3K4 methylation has been linked to transcriptional activation. JARID1A (also known as RBP2 or KDM5A), a member of the JARID1 protein family, is an H3K4 demethylase, previously implicated in the regulation of transcription and differentiation. Here we show that JARID1A is physically and functionally associated with two histone deacetylase complexes. Immunoaffinity purification of JARID1A confirmed a previously described association with the SIN3B-containing HDAC complex, and revealed an association with the nucleosome remodeling and deacetylase (NuRD) complex. Sucrose density gradient and sequential immunoprecipitation analyses further confirmed the stable association of JARID1A with these two HDAC complexes. JARID1A depletion led to changes in the expression of hundreds of genes, two-thirds of which were also controlled by CHD4, the NuRD catalytic subunit. Gene ontology analysis confirmed that the genes commonly regulated by both JARID1A and CHD4 were categorized as developmentally regulated genes. ChIP analyses suggested that CHD4 controls chromatin association with JARID1A and modulates H3K4 levels at the promoter and coding regions of target genes. We further demonstrated that the C. elegans homologues of JARID1 and CHD4 function in the same pathway during vulva development. Taken together, these results suggest that JARID1A and the NuRD complex cooperatively function to control developmentally regulated genes. Genome-wide transcriptomic analysis of HeLa cells transfected with JARID1A complex component siRNA

ORGANISM(S): Homo sapiens

SUBMITTER: Jun-ichi Nakayama

PROVIDER: E-GEOD-55206 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Physical and functional interactions between the histone H3K4 demethylase JARID1A and the NuRD complex

Project description:Histone H3K4 methylation has been linked to transcriptional activation. JARID1A (also known as RBP2 or KDM5A), a member of the JARID1 protein family, is an H3K4 demethylase, previously implicated in the regulation of transcription and differentiation. Here we show that JARID1A is physically and functionally associated with two histone deacetylase complexes. Immunoaffinity purification of JARID1A confirmed a previously described association with the SIN3B-containing HDAC complex, and revealed an association with the nucleosome remodeling and deacetylase (NuRD) complex. Sucrose density gradient and sequential immunoprecipitation analyses further confirmed the stable association of JARID1A with these two HDAC complexes. JARID1A depletion led to changes in the expression of hundreds of genes, two-thirds of which were also controlled by CHD4, the NuRD catalytic subunit. Gene ontology analysis confirmed that the genes commonly regulated by both JARID1A and CHD4 were categorized as developmentally regulated genes. ChIP analyses suggested that CHD4 controls chromatin association with JARID1A and modulates H3K4 levels at the promoter and coding regions of target genes. We further demonstrated that the C. elegans homologues of JARID1 and CHD4 function in the same pathway during vulva development. Taken together, these results suggest that JARID1A and the NuRD complex cooperatively function to control developmentally regulated genes.

2014-02-21 | GSE55206 | GEO

Promoter Decommissioning by the NuRD Chromatin Remodeling Complex Triggers Synaptic Connectivity in the Mammalian Brain

Project description:Precise control of gene expression plays fundamental roles in brain development, but the roles of chromatin regulators in neuronal connectivity have remained poorly understood. Here, we find that depletion of the nucleosome remodeling and deacetylation (NuRD) complex in the cerebellar cortex by in vivo RNAi in rats and conditional knockout of the core NuRD subunit Chd4 in mice profoundly impairs the establishment of granule neuron parallel fiber/Purkinje cell synapses. In RNA-Seq analyses of Chd4 conditional knockout mice, we identify a set of nearly 200 genes that are repressed by the NuRD complex in the cerebellum in vivo. Genome-wide ChIP-Seq analyses reveal that the NuRD complex selectively decommissions the promoters of NuRD-repressed genes in the cerebellum in vivo by inducing the deacetylation of histone H3K9/14 and H3K27 and demethylation of H3K4 at these genes. Importantly, temporal control of promoter decommissioning and repression of NuRD target genes upon maturation of the cerebellum requires the NuRD complex. Finally, in a targeted in vivo RNAi screen of NuRD-repressed target genes, we identify the transcription factor Nhlh1, the RNA-binding protein Elavl2, and the presynaptic regulator Cplx3 as negative regulators of presynaptic differentiation in the cerebellar cortex. Together, these findings define NuRD-dependent promoter decommissioning as a developmentally regulated programming mechanism that releases the brake on presynaptic differentiation and thereby drives synaptic connectivity in the mammalian brain. Three distinct histone modifications using postnatal day 6 or day 22 cerebella from wild type (WT) or Chd4 conditional knockout (cKO) mice were examined in duplicate using libraries prepared with the Illumina ChIP-Seq DNA Sample Prep Kit and sequenced on the Illumina HiSeq 2000 platform.

2014-08-18 | E-GEOD-57758 | biostudies-arrayexpress

Promoter Decommissioning by the NuRD Chromatin Remodeling Complex Triggers Synaptic Connectivity in the Mammalian Brain

2014-08-18 | GSE57758 | GEO

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

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

Homo sapiens

Project description:Physical and functional interactions between the histone H3K4 demethylase JARID1A and the NuRD complex

| PRJNA238942 | ENA

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

Chromatin Remodeling Inactivates Activity Genes and Regulates Neural Coding

Project description:Activity-dependent transcription influences neuronal connectivity, but the roles and mechanisms of inactivation of activity-dependent genes have remained poorly understood. Genome-wide analyses in the mouse cerebellum revealed that the nucleosome remodeling and deacetylase (NuRD) complex deposits the histone variant H2A.z at promoters of activity-dependent genes, thereby triggering their inactivation. Purification of translating mRNAs from synchronously developing granule neurons (Sync-TRAP) showed that conditional knockout of the core NuRD subunit Chd4 impairs inactivation of activity-dependent genes when neurons undergo dendrite pruning. Chd4 knockout or expression of NuRD-regulated activity genes impairs dendrite pruning. Imaging of behaving mice revealed hyperresponsivity of granule neurons to sensorimotor stimuli upon Chd4 knockout. Our findings define an epigenetic mechanism that inactivates activity-dependent transcription and regulates dendrite patterning and sensorimotor encoding in the brain. One or two replicates of the histone modifications (H3K27me3 and H2A.z), total histone proteins (H2A.z and H3), and ATPase Chd4 using postnatal day 22 cerebella from wild type (WT) or Chd4 conditional knockout (cKO) mice were examined using libraries prepared with the Illumina ChIP-Seq DNA Sample Prep Kit. Four replicates of total RNA were extracted from postnatal day 27-28 cerebella from rotarod-trained or control homecage mice, or Chd4 cKO or WT mice using Trizol and reverse-transcribed with oligo-dT priming. Three replicates of immunoprecipitated Sync-TRAP RNA or the input control using postnatal day 12 Chd4 cKO or WT cerebella were purified and amplified with Ovation RNA-Seq System V2 (NuGEN). All samples were sequenced on the Illumina HiSeq 2000 platform.

2016-07-18 | E-GEOD-83253 | biostudies-arrayexpress

P15 Rat Sciatic Nerve ChIP-Chip with NuRD complex components

Project description:The NuRD complex is required for efficient and timely myelination in the peripheral nervous system. ChIP-chip assays were performed on rat sciatic nerve at P15, a peak timepoint of myelination, for binding of Chd4 to genes involved in regulating myelin formation. This experiment includes two custom ChIP-chip design incorporating many genes that are dynamically regulated during myelination. The antibodies used in this platform were Chd3/4 (Santa Cruz sc-11378) Chd4 (gift from Paul Wade), Mta2 (Santa Cruz sc-9447), and Nab2 (Santa Cruz sc-22815). Chd4 ChIP samples from experimental and input samples were hybridized.

2011-07-25 | E-GEOD-30890 | 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

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