XIST and MUC1-C form an autoregulatory pathway in driving cancer progression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1097636 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28590266_1.fastq.gz | Fastqsanger.gz | |||
| SRR28590266_2.fastq.gz | Fastqsanger.gz | |||
| SRR28590267_1.fastq.gz | Fastqsanger.gz | |||
| SRR28590267_2.fastq.gz | Fastqsanger.gz | |||
| SRR28590268_1.fastq.gz | Fastqsanger.gz |
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Project description:MUC1-C /XIST autoregulatory axis is of importance in cancer progression where MUC1-C regulates XIST lncRNA levels in cancer
2024-12-04 | GSE263487 | GEO
Project description:Nuclear compartments play diverse roles in regulating gene expression, yet the molecular forces and components driving compartment formation are not well understood. Studying how the lncRNA Xist establishes the inactive-X-chromosome (Xi)-compartment, we found that the Xist RNA-binding-proteins PTBP1, MATR3, TDP43, and CELF1 form a condensate to create an Xi-domain that can be sustained in the absence of Xist. The E-repeat-sequence of Xist serves a multivalent binding-platform for these proteins. Without the E-repeat, Xist initially coats the X-chromosome during XCI onset but subsequently disperses across the nucleus with loss of gene silencing. Recruitment of PTBP1, MATR3, TDP-43 or CELF1 to E-Xist rescues these phenotypes, and requires both self-association of MATR3 and TDP-43 and a heterotypic PTBP1-MATR3-interaction. Together, our data reveal that Xist sequesters itself within the Xi-territory and perpetuates gene silencing by seeding a protein-condensate. Our findings uncover an unanticipated mechanism for epigenetic memory and elucidate the interplay between RNA and RNA-binding-proteins in creating compartments for gene regulation.
2020-09-03 | GSE137305 | GEO
Project description:STAT1 and IRF1 are essential effectors of the type I and II interferon (IFN) pathways. Here, we report that the oncogenic MUC1-C protein is necessary for inducing chromatin accessibility and activation of the STAT1 and IRF1 genes in triple-negative breast cancer (TNBC) cells. Our results demonstrate that MUC1-C activates the PBRM1 subunit of the SWI/SNF PBAF chromatin remodeling complex and forms a nuclear complex with PBRM1. We show that MUC1-C associates with PBRM1 and STAT1 on the IRF1 gene at (i) a proximal enhancer-like signature (PLS), and (ii) distal enhancer-like signatures (dELSs). We also show MUC1-C and PBRM1 are necessary for opening chromatin at these signatures and for the induction of IRF1 expression. In extending these results, we found that MUC1-C binds directly to IRF1 and forms nuclear complexes with PBRM1 and IRF1, which are necessary for inducing chromatin accessibility at PLS of the (i) STAT1 gene, (ii) type II IFN pathway IDO1 and WARS genes, and (iii) type I IFN pathway RIG-I, MDA5 and ISG15 genes. Consistent with involvement of chronic inflammation in promoting the cancer stem cell (CSC) state, we show that MUC1-C, PBRM1 and IRF1 are required for self-renewal of TNBC CSCs. Of translational relevance, we report that targeting MUC1-C, PBRM1 and IRF1 circumvents intrinsic DNA damage resistance of TNBC CSCs and that MUC1-C is necessary for acquired resistance to the PARP inhibitor olaparib. These findings demonstrate that MUC1-C activates PBRM1/IRF1 and thereby chromatin remodeling of IFN pathway genes that promote chronic inflammation, the CSC state and DNA damage resistance.
2023-06-14 | GSE212587 | GEO
Project description:Latent Epstein-Barr Virus (EBV) infection promotes cancers derived from B-lymphocytes and epithelial cells. EBV-encoded nuclear antigen 1 (EBNA1) is uniformly expressed in EBV-associated cancers. The MUC1 gene evolved in mammals to protect barrier tissues from viral infections. We report that MUC1 and the encoded oncogenic MUC1-C protein are upregulated in EBV-associated gastric cancers (EBVaGCs). We demonstrate that EBNA1 forms a complex with MUC1-C that regulates EBNA1 and MUC1-C expression. EBNA1 appropriates MUC1-C for (i) inducing DNA methyltransferases and DNA methylation, (ii) suppressing p21 and driving cell cycle progression, (iii) increasing survivin in promoting survival, and (iv) regulating MYC as an effector of EBV latency. MUC1-C thereby functions in maintaining EBV episomes and regulating EBV latency and lytic genes. In regard to EBVaGC progression, MUC1-C regulates expression of the SOX2 and NOTCH1-3 stemness genes, self-renewal capacity, and tumorigenicity. These findings indicate that EBNA1 co-opts MUC1-C functions that promote EBV latency and that MUC1-C is necessary for EBVaGC pathogenesis.
2024-06-28 | GSE270984 | GEO
Project description:Purpose: Compare the transcriptome of homogeneous XIST+ and XIST- hES cell populations. Methods: We isolated homogeneous XIST+ and XIST- cell populations. The XIST+ cells correspond to cells with a XIST cloud and one ATRX pinpoint. The XIST- cells correspond to cells with no XIST cloud and one ATRX pinpoint. Results: We took advantage of the clonal pattern of X-chromosome inactivation in H9 cells and analyzed the data in an allelic manner. By comparing the RNA-Seq data with known H9 SNPs, we identified genomic positions which were relaxed from XCI in XIST- cells compared to XIST+ cells. Conclusions: Genic as well as unannotated transcripts are massively relaxed from XCI in H9 cells when XIST expression is lost, however, this reactivation is only partial and a large region around the centromere is protected from relaxation of silencing. Total RNA (rRNA depleted) profiles of XIST+ and XIST- human embryonic stem cells
2012-12-21 | E-GEOD-39757 | biostudies-arrayexpress
Project description:Mucin 1 (MUC1) is a transmembrane mucin expressed at the apical surface of epithelial cells at different mucosal surfaces including breast and intestine. The MUC1 extracellular domain contains a variable number of tandem repeats (VNTR) of 20 amino acids, which are heavily O-linked glycosylated. Monoclonal antibodies against the MUC1 VNTR can be powerful tools because of their multiplicity of binding and possible applications in the diagnosis and treatment of MUC1-expressing cancers. One such antibody is the hybridoma mouse monoclonal 139H2 which is also widely used as a research tool to study non-cancer MUC1. Here we report direct mass spectrometry-based sequencing of hybridoma-derived 139H2 IgG, which enabled reverse engineering of a recombinant 139H2.
2024-03-18 | PXD043489 | Pride
Project description:STAT1 and IRF1 are essential effectors of the type I and II interferon (IFN) pathways. Here, we report that the oncogenic MUC1-C protein is necessary for inducing chromatin accessibility and activation of the STAT1 and IRF1 genes in triple-negative breast cancer (TNBC) cells. Our results demonstrate that MUC1-C activates the PBRM1 subunit of the SWI/SNF PBAF chromatin remodeling complex and forms a nuclear complex with PBRM1. We show that MUC1-C associates with PBRM1 and STAT1 on the IRF1 gene at (i) a proximal enhancer-like signature (pELS), and (ii) distal enhancer-like signatures (dELSs). We also show MUC1-C and PBRM1 are necessary for opening chromatin at these signatures and for the induction of IRF1 expression. In extending these results, we found that MUC1-C binds directly to IRF1 and forms nuclear complexes with PBRM1 and IRF1, which are necessary for inducing chromatin accessibility at pELSs of the (i) STAT1 gene, (ii) type II IFN pathway IDO1 and WARS genes, and (iii) type I IFN pathway RIG-I, MDA5 and ISG15 genes. Consistent with involvement of chronic inflammation in promoting the cancer stem cell (CSC) state, we show that MUC1-C, PBRM1 and IRF1 are required for self-renewal of TNBC CSCs. Of translational relevance, we report that targeting MUC1-C, PBRM1 and IRF1 circumvents intrinsic DNA damage resistance of TNBC CSCs and that MUC1-C is necessary for acquired resistance to the PARP inhibitor olaparib. These findings demonstrate that MUC1-C activates PBRM1 and thereby chromatin remodeling of IFN pathway genes that promote chronic inflammation, the CSC state and DNA damage resistance.
2022-06-21 | GSE206212 | GEO
Project description:Neuroendocrine prostate cancer (NEPC) is a highly aggressive malignancy of increasing prevalence with an unmet need for targeted therapeutic approaches. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC; however, there is no known role for MUC1-C in driving lineage plasticity to these advanced PC phenotypes. The present studies demonstrate that upregulation of MUC1-C in androgen-independent (AI) PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor by a previously unrecognized MYC-mediated mechanism. MUC1-C activates the BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP), which are linked to NEPC progression. We also show that MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Of potential clinical relevance, targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, supporting the treatment of CRPC and NEPC with agents directed against this oncoprotein. These findings and the demonstration that MUC1-C is upregulated and associated with suppression of AR signaling, and increases in BRN2 expression and the NEPC score in PC tissues highlight the unanticipated importance of MUC1-C as a master effector of lineage plasticity in progression to advanced PC with NE features.
2019-12-02 | GSE139335 | GEO
Project description:STAT1 and IRF1 are essential effectors of the type I and II interferon (IFN) pathways. Here, we report that the oncogenic MUC1-C protein is necessary for inducing chromatin accessibility and activation of the STAT1 and IRF1 genes in triple-negative breast cancer (TNBC) cells. Our results demonstrate that MUC1-C activates the PBRM1 subunit of the SWI/SNF PBAF chromatin remodeling complex and forms a nuclear complex with PBRM1. We show that MUC1-C associates with PBRM1 and STAT1 on the IRF1 gene at (i) a proximal enhancer-like signature (PLS), and (ii) distal enhancer-like signatures (dELSs). We also show MUC1-C and PBRM1 are necessary for opening chromatin at these signatures and for the induction of IRF1 expression. In extending these results, we found that MUC1-C binds directly to IRF1 and forms nuclear complexes with PBRM1 and IRF1, which are necessary for inducing chromatin accessibility at PLS of the (i) STAT1 gene, (ii) type II IFN pathway IDO1 and WARS genes, and (iii) type I IFN pathway RIG-I, MDA5 and ISG15 genes. Consistent with involvement of chronic inflammation in promoting the cancer stem cell (CSC) state, we show that MUC1-C, PBRM1 and IRF1 are required for self-renewal of TNBC CSCs. Of translational relevance, we report that targeting MUC1-C, PBRM1 and IRF1 circumvents intrinsic DNA damage resistance of TNBC CSCs and that MUC1-C is necessary for acquired resistance to the PARP inhibitor olaparib. These findings demonstrate that MUC1-C activates PBRM1/IRF1 and thereby chromatin remodeling of IFN pathway genes that promote chronic inflammation, the CSC state and DNA damage resistance.
2023-06-14 | GSE212168 | GEO
Project description:STAT1 and IRF1 are essential effectors of the type I and II interferon (IFN) pathways. Here, we report that the oncogenic MUC1-C protein is necessary for inducing chromatin accessibility and activation of the STAT1 and IRF1 genes in triple-negative breast cancer (TNBC) cells. Our results demonstrate that MUC1-C activates the PBRM1 subunit of the SWI/SNF PBAF chromatin remodeling complex and forms a nuclear complex with PBRM1. We show that MUC1-C associates with PBRM1 and STAT1 on the IRF1 gene at (i) a proximal enhancer-like signature (PLS), and (ii) distal enhancer-like signatures (dELSs). We also show MUC1-C and PBRM1 are necessary for opening chromatin at these signatures and for the induction of IRF1 expression. In extending these results, we found that MUC1-C binds directly to IRF1 and forms nuclear complexes with PBRM1 and IRF1, which are necessary for inducing chromatin accessibility at PLS of the (i) STAT1 gene, (ii) type II IFN pathway IDO1 and WARS genes, and (iii) type I IFN pathway RIG-I, MDA5 and ISG15 genes. Consistent with involvement of chronic inflammation in promoting the cancer stem cell (CSC) state, we show that MUC1-C, PBRM1 and IRF1 are required for self-renewal of TNBC CSCs. Of translational relevance, we report that targeting MUC1-C, PBRM1 and IRF1 circumvents intrinsic DNA damage resistance of TNBC CSCs and that MUC1-C is necessary for acquired resistance to the PARP inhibitor olaparib. These findings demonstrate that MUC1-C activates PBRM1/IRF1 and thereby chromatin remodeling of IFN pathway genes that promote chronic inflammation, the CSC state and DNA damage resistance.
2023-06-14 | GSE212169 | GEO