Progressive intestinal tumor cell plasticity, Myc activation and loss of Lgr5+ tumor stem cell lineage commitment upon Wnt depletion
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE288156 | GEO | 2026/04/27
REPOSITORIES: GEO
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Project description:Progressive intestinal tumor cell plasticity, Myc activation and loss of Lgr5+ tumor stem cell lineage commitment upon Wnt depletion
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Project description:Osteoblast differentiation leading to bone formation requires a coordinated transcriptional program. We have recently demonstrated that microtubule actin crosslinking factor 1 (MACF1) promotes osteoblast differentiation, suggesting a key role in regulating early-phase osteoblast differentiation. Here, we showed that the early-phase osteoblast differentiation transcriptome dynamics was regulated by MACF1 and the transcription of TCF7/LEF1, key effectors of Wnt signaling that is important for osteoblast differentiation was suppressed by MACF1 knockdown. Co-IP and Protein mass spectrometry revealed that MACF1 interacted with a known and two previously unknown repressors of TCF7/LEF1, DKK1, CDK12 and MEAF6. ChIP-seq analysis of MACF1-associated promoters further revealed that MACF1 interacted with transcription factors TCF12 and E2F6, which also suppressed the transcription of TCF7/LEF1. Furthermore, all these four MACF-interacted proteins inhibited osteoblast differentiation. By studying the underlying mechanism, we found that cytoplasmic-nuclear localization of MACF1 was dependent on its level and the cytoplasmic-nuclear localization of TCF12 and E2F6 was regulated by MACF1 localization. In addition, MACF1 oppositely regulated the transcription activity of TCF12 and TCF7. Current study, for the first time to our knowledge, suggest that MACF1 acts as a sponge of osteoblast differentiation repressors to promote osteoblast differentiation, and indicate a novel mechanism for regulating the cellular location of transcription factors by a protein associated with microtubule and actin.
2021-02-17 | GSE120248 | GEO
Project description:Osteoblast differentiation leading to bone formation requires a coordinated transcriptional program. We have recently demonstrated that microtubule actin crosslinking factor 1 (MACF1) promotes osteoblast differentiation, suggesting a key role in regulating early-phase osteoblast differentiation. Here, we showed that the early-phase osteoblast differentiation transcriptome dynamics was regulated by MACF1 and the transcription of TCF7/LEF1, key effectors of Wnt signaling that is important for osteoblast differentiation was suppressed by MACF1 knockdown. Co-IP and Protein mass spectrometry revealed that MACF1 interacted with a known and two previously unknown repressors of TCF7/LEF1, DKK1, CDK12 and MEAF6. ChIP-seq analysis of MACF1-associated promoters further revealed that MACF1 interacted with transcription factors TCF12 and E2F6, which also suppressed the transcription of TCF7/LEF1. Furthermore, all these four MACF-interacted proteins inhibited osteoblast differentiation. By studying the underlying mechanism, we found that cytoplasmic-nuclear localization of MACF1 was dependent on its level and the cytoplasmic-nuclear localization of TCF12 and E2F6 was regulated by MACF1 localization. In addition, MACF1 oppositely regulated the transcription activity of TCF12 and TCF7. Current study, for the first time to our knowledge, suggest that MACF1 acts as a sponge of osteoblast differentiation repressors to promote osteoblast differentiation, and indicate a novel mechanism for regulating the cellular location of transcription factors by a protein associated with microtubule and actin.
2021-02-17 | GSE120251 | GEO
Project description:In most cell types, nuclear β-catenin functions as prominent oncogenic driver and pairs with TCF7-family factors for transcriptional activation of MYC. Surprisingly, B-lymphoid malignancies not only lacked expression and activating lesions of β-catenin but critically depended on GSK3b for effective b-catenin degradation. Our interactome studies in B-lymphoid tumors revealed that b-catenin formed repressive complexes with lymphoid-specific Ikaros and Lef1 factors at the expense of TCF7. While Lef1 was critical for nuclear β-catenin translocation, nuclear b-catenin enabled Ikaros-mediated recruitment of nucleosome remodeling and deacetylation (NuRD) complexes for transcriptional repression of MYC.
2025-08-08 | GSE245287 | GEO
Project description:Cholangiocarcinoma (CCA) is a devastating liver cancer characterized by high aggressiveness and resistance to therapy, which results to poor prognosis. Signals imposed by oncogenic pathways, such as transforming growth factor β (TGFβ) frequently contribute to CCA development. In this study, we explored novel effectors of the TGFβ pathway in CCA by gene expression profiling. We identified the long non-coding RNA LINC00313 as a novel target gene of TGFβ signalling in CCA cells. TGFβ induced LINC00313 expression in a TβRI/Smad-dependent manner. Subcellular fractionation showed that LINC00313 is a predominantly nuclear lncRNA. By integrating RNA-seq and ATAC-seq data from LINC00313 over-expressing cells, we observed that LINC00313 regulates the expression of several genes involved in the Wnt signalling pathway. As a proof of concept, we focused on the gene encoding transcription factor 7 (TCF7), a major effector that drives transcription of Wnt-target genes. LINC00313 gain of function resulted in increased TCF7 expression, while its loss of function diminished basal or TGFβ-induced TCF7 expression levels. Interestingly, LINC00313 enhanced basal or chemically induced TCF/LEF-dependent transcriptional responses, promoted colony-forming capacities of CCA cells in vitro and accelerated tumor growth in vivo. We also report that genes associated with LINC00313 over-expression recapitulate poor prognosis human CCA associated with a reduced overall survival and KRAS mutations. To decipher the underlying molecular functions of LINC00313, we identified its interacting proteins by performing an unbiased RNA pull-down assay followed by mass spectrometry. We demonstrated that actin-like 6A (ACTL6A), a subunit of the SWI/SNF chromatin remodelling complex specifically binds to LINC00313 and impacts TCF7 expression and TCF/LEF signalling output. Thus, we propose a model whereby TGFβ induces LINC00313, in order to regulate the expression of a subset of target genes, such as TCF7 possibly in co-operation with the SWI/SNF chromatin remodelling complex, via establishing direct interaction with ACTL6A. By regulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and boosts cholangiocarcinogenesis.
2024-02-05 | E-MTAB-12879 | biostudies-arrayexpress
Project description:Cholangiocarcinoma (CCA) is a devastating liver cancer characterized by high aggressiveness and resistance to therapy, which results to poor prognosis. Signals imposed by oncogenic pathways, such as transforming growth factor β (TGFβ) frequently contribute to CCA development. In this study, we explored novel effectors of the TGFβ pathway in CCA by gene expression profiling. We identified the long non-coding RNA LINC00313 as a novel target gene of TGFβ signalling in CCA cells. TGFβ induced LINC00313 expression in a TβRI/Smad-dependent manner. Subcellular fractionation showed that LINC00313 is a predominantly nuclear lncRNA. By integrating RNA-seq and ATAC-seq data from LINC00313 over-expressing cells, we observed that LINC00313 regulates the expression of several genes involved in the Wnt signalling pathway. As a proof of concept, we focused on the gene encoding transcription factor 7 (TCF7), a major effector that drives transcription of Wnt-target genes. LINC00313 gain of function resulted in increased TCF7 expression, while its loss of function diminished basal or TGFβ-induced TCF7 expression levels. Interestingly, LINC00313 enhanced basal or chemically induced TCF/LEF-dependent transcriptional responses, promoted colony-forming capacities of CCA cells in vitro and accelerated tumor growth in vivo. We also report that genes associated with LINC00313 over-expression recapitulate poor prognosis human CCA associated with a reduced overall survival and KRAS mutations. To decipher the underlying molecular functions of LINC00313, we identified its interacting proteins by performing an unbiased RNA pull-down assay followed by mass spectrometry. We demonstrated that actin-like 6A (ACTL6A), a subunit of the SWI/SNF chromatin remodelling complex specifically binds to LINC00313 and impacts TCF7 expression and TCF/LEF signalling output. Thus, we propose a model whereby TGFβ induces LINC00313, in order to regulate the expression of a subset of target genes, such as TCF7 possibly in co-operation with the SWI/SNF chromatin remodelling complex, via establishing direct interaction with ACTL6A. By regulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and boosts cholangiocarcinogenesis.
2024-02-05 | E-MTAB-12030 | biostudies-arrayexpress
Project description: Not available
| S-EPMC3372227 | biostudies-literature
Project description:Transcriptomic data related to 4 different subpopulations found in Mex3a Ki/+ Lgr5 Gfp in APCflfl adenomas in untreated animals. Adenomas where induced with 3%DSS and a single shot of 8mg/kg of Tamoxifen. The populations are refered as Mex3a + Lgr5, Mex3a- Lgr5+ Mex3a+ Lgr5- and Mex3a- Lgr5- according to the flow cytometry profile. Cells were isolated using FACsARIA (BD)
2022-05-12 | GSE163171 | GEO
Project description:Somatic mutations in APC or CTNNB1 genes lead to aberrant Wnt signaling and colorectal cancer (CRC) initiation and progression. Activation of Wnt pathway leads to the formation of beta-catenin-T-cell factor/Lymphoid enhancer binding factor 1 (Tcf/Lef1) complexes that activate transcription of oncogenic target genes. Lef1 is the only member of the Tcf gene family that is not expressed in the normal intestine, but is induced during intestinal tumorigenesis. Thus, we wanted to assess the role of Lef1 using genetic mouse models of intestinal adenomas and scRNA-seq technology. Tumorigenesis was initiated by inducing Apc mutation in Lgr5+ stem cells. Intestinal EpCAM+ epithelial cells of Lgr5-CreERT;Apc fl/fl (LApc) mouse and Lgr5-CreERT;Apc fl/fl; Lef1 fl/fl (LApcL) mouse were used to analyze the effects of Lef1 deletion in intestinal adenoma cells. We used WT mice as a control to distinguish adenoma cells.
2021-12-10 | GSE179483 | GEO
Project description: Not available
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