Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

MUC1-C ACTIVATES THE NURD COMPLEX IN DEDIFFERENTIATION OF TRIPLE-NEGATIVE BREASTCANCER CELLS

ABSTRACT: The NuRD chromatin remodeling and deacetylation complex, which includes MTA1, MBD3, CHD4 and HDAC1 among other components, is of importance for development and cancer progression. The oncogenic MUC1-C protein activates EZH2 and BMI1 in the epigenetic reprogramming of triple-negative breast cancer (TNBC) cells. However, there is no known link between MUC1-C and chromatin remodeling complexes. The present studies demonstrate that MUC1-C binds directly to the MYC HLH/LZ domain. In turn, we identified a previously unrecognized MUC1-C®MYC pathway that regulates the NuRD complex. We show that MUC1-C/MYC complexes selectively activate the MTA1 and MBD3 genes and posttranscriptionally induce CHD4 expression in basal- and not luminal-type BC cells. The results further show that MUC1-C forms complexes with these NuRD components on the ESR1 promoter. In this way, silencing MUC1-C (i) decreased MTA1/MBD3/CHD4/HDAC1 occupancy and increased H3K27 acetylation on the ESR1 promoter, and (ii) induced ESR1 expression and downstream estrogen response pathways. We also demonstrate that targeting MUC1-C and these NuRD components induces expression of FOXA1, GATA3 and other markers associated with the luminal phenotype. These findings and results from gain-of-function studies support a model in which MUC1-C activates the NuRD complex in driving luminal®basal dedifferentiation and plasticity of TNBC cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE134147 | GEO | 2020/03/05

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

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

A variant NuRD complex containing PWWP2A/B excludes MBD2/3 to regulate transcription at active genes

Project description:Transcriptional regulation by chromatin is a highly dynamic process directed through the recruitment and coordinated action of epigenetic modifiers and readers of these modifications. Using an unbiased proteomic approach to find interactors of H3K36me3, a modification enriched on active chromatin, we identify PWWP2A and HDAC2 among the top interactors. PWWP2A and its paralog PWWP2B form a stable complex with NuRD subunits MTA1/2/3:HDAC1/2:RBBP4/7, but not with MBD2/3, p66α/β, and CHD3/4. PWWP2A competes with MBD3 for binding to MTA1, thus defining a new variant NuRD complex that is mutually exclusive with the MBD2/3-containing NuRD. In mESCs, PWWP2A/B is most enriched at highly transcribed genes. Loss of PWWP2A/B leads to increases in histone acetylation predominantly at highly expressed genes, accompanied by decreases in Pol II elongation. Collectively, these findings suggest a role for PWWP2A/B in regulating transcription through the fine-tuning of histone acetylation dynamics at actively transcribed genes.

2018-07-19 | PXD010445 | Pride

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

2013-10-31 | GSE51097 | 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

Nascent transcription of E14, PWWP2AKO, and PWWP2A/B DKO

Project description:Transcriptional regulation by chromatin is a highly dynamic process directed through the recruitment and coordinated action of epigenetic modifiers and readers of these modifications. Using an unbiased proteomic approach to find interactors of H3K36me3, a modification enriched on active chromatin, here we identify PWWP2A and HDAC2 among the top interactors. PWWP2A and its paralog PWWP2B form a stable complex with NuRD subunits MTA1/2/3:HDAC1/2:RBBP4/7, but not with MBD2/3, p66α/β, and CHD3/4. PWWP2A competes with MBD3 for binding to MTA1, thus defining a new variant NuRD complex that is mutually exclusive with the MBD2/3-containing NuRD. In mESCs, PWWP2A/B is most enriched at highly transcribed genes. Loss of PWWP2A/B leads to increases in histone acetylation predominantly at highly expressed genes, accompanied by decreases in Pol II elongation. Collectively, these findings suggest a role for PWWP2A/B in regulating transcription through the fine-tuning of histone acetylation dynamics at actively transcribed genes.

2018-07-20 | GSE112112 | GEO

A variant NuRD complex containing PWWP2A/B excludes MBD2/3 and directs HDAC activity to regulate histone acetylation and RNA Pol II dynamics

Project description:Transcriptional regulation by chromatin is a highly dynamic process directed through the recruitment and coordinated action of epigenetic modifiers and readers of these modifications. Using an unbiased proteomic approach to find interactors of H3K36me3, a modification enriched on active chromatin, here we identify PWWP2A and HDAC2 among the top interactors. PWWP2A and its paralog PWWP2B form a stable complex with NuRD subunits MTA1/2/3:HDAC1/2:RBBP4/7, but not with MBD2/3, p66α/β, and CHD3/4. PWWP2A competes with MBD3 for binding to MTA1, thus defining a new variant NuRD complex that is mutually exclusive with the MBD2/3-containing NuRD. In mESCs, PWWP2A/B is most enriched at highly transcribed genes. Loss of PWWP2A/B leads to increases in histone acetylation predominantly at highly expressed genes, accompanied by decreases in Pol II elongation. Collectively, these findings suggest a role for PWWP2A/B in regulating transcription through the fine-tuning of histone acetylation dynamics at actively transcribed genes.

2018-07-20 | GSE112113 | GEO

Zic2, an enhancer-binding factor required for embryonic stem cell specification

Project description:The Zinc finger protein of the cerebellum 2 (Zic2) is one of the vertebrate homologs of the Drosophila pair-rule gene odd-paired (opa). Our molecular and biochemical studies have demonstrated that Zic2 to preferentially bind to transcriptional enhancers and functions as a cofactor that interacts with the NuRD complex in ES cells. Detailed genome-wide studies demonstrate that Zic2 function with Mbd3/NuRD in regulating the chromatin state and transcriptional output of genes linked to differentiation. Zic2 is dispensable for the selfrenewal of ES cells but is required for proper differentiation, similar to what has been previously reported for Mbd3/NuRD. Our study identifies Zic2 as a key factor in the execution of the pluripotency program with Mbd3/NuRD in ES cells. ChIP-seq of Zic2, Chd4, Mbd3 and Zic3 in mES cells. ChIP-seq of H3K27me3, H3K27ac, H3K4me3, H3K4me1 and PolII in mES cells after Zic2 shRNA and non-targeting shRNA. RNA-seq of mES cells after Zic2, Zic3, Mbd3 and Mta2 shRNA and non-targeting shRNA.

2015-02-23 | E-GEOD-61188 | 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

Genome-wide identification of MBD2 and MBD3 binding sites by ChIP-seq

Project description:The heterogeneous collection of NuRD complexes can be grouped into the MBD2 or MBD3 containing complexes MBD2-NuRD and MBD3-NuRD. Although functional differences have been described, a direct comparison of MBD2 and MBD3 in respect to genome-wide binding and function has been lacking. Here we show a strong enrichment for MBD2 at methylated CpG sequences, whereas CpGs bound by MBD3 are devoid of methylation. Gene activity of MBD2 bound genes is four fold lower as compared to genes bound by MBD3. When depleting cells for MBD2, the MBD2 bound genes increase their activity, whereas MBD2 plus MBD3 bound genes reduce their activity. Most strikingly, MBD3 is enriched at active promoters, whereas MBD2 is bound at methylated promoters and enriched at exon sequences of active genes. This suggests a functional connection between MBD2 binding to chromatin and splicing. V5 ChIP followed by high throughput sequencing in HeLa cells transiently transfected with either V5-MBD2b, V5-MBD3 or V5.

2013-02-08 | E-GEOD-41006 | biostudies-arrayexpress

Expression data from HeLa cells after MBD2 and MBD3 knock down

Project description:The heterogeneous collection of NuRD complexes can be grouped into the MBD2 or MBD3 containing complexes MBD2-NuRD and MBD3-NuRD. MBD2 is known to bind to methylated CpG sequences in vitro in contrast to MBD3. Although functional differences have been described, a direct comparison of MBD2 and MBD3 in respect to genome-wide binding and function has been lacking. Here we show when depleting cells for MBD2, the MBD2 bound genes increase their activity, whereas MBD2 plus MBD3 bound genes reduce their activity. Most strikingly, MBD3 is enriched at active promoters, whereas MBD2 is bound at methylated promoters and enriched at exon sequences of active genes. This suggests a functional connection between MBD2 binding to chromatin and splicing. 9 Total samples were analysed. Three individual replicates for HeLa cells treated with siRNA against MBD2, MBD3 or scrambled siRNA were performed. We calculated the fold change of gene expression of cells treated with MBD2- or MBD3-siRNA over cells treated with scrambled siRNA.

2013-02-08 | E-GEOD-41003 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data