Elevated GRHL2 imparts plasticity in estrogen receptor positive breast cancer cells [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1134762 | ENA |
REPOSITORIES: ENA
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Project description:Elevated GRHL2 imparts plasticity in estrogen receptor positive breast cancer cells [ChIP-Seq]
| PRJNA1134764 | ENA
Project description:Estrogen receptor (ER) positive breast cancer is characterized by a late recurrence following initial treatment. The epithelial cell fate transcription factor Grainyhead-like protein 2 (GRHL2) is amplified in ER positive breast cancers and is indicative of poorer prognosis as compared to ER negative breast cancer. To understand how GRHL2 contributes to progression, GRHL2 was overexpressed in ER positive cells. To examine gene expression changes from elevated GRHL2 levels, RNA-sequencing was performed to better comprehend how high GRHL2 may change its transcriptional activity.
2024-08-25 | GSE272061 | GEO
Project description:Estrogen receptor (ER) positive breast cancer is characterized by a late recurrence following initial treatment. The epithelial cell fate transcription factor Grainyhead-like protein 2 (GRHL2) is amplified in ER positive breast cancers and is indicative of poorer prognosis as compared to ER negative breast cancer. To understand how GRHL2 contributes to progression, GRHL2 was overexpressed in ER positive cells. To determine how GRHL2 overexpression affects GRHL2 binding to DNA, ChIP sequencing was conducted to evaluate binding intensity and location.
2024-08-25 | GSE272059 | GEO
Project description:Phosphorylation of estrogen receptor α (ER) at serine 118 (pS118-ER) is induced by estrogen and is the most abundant post-translational mark associated with a transcriptionally active receptor. Cistromic analysis of pS118-ER from our group found enrichment of the GRHL2 motif near pS118-ER binding sites. In this report we use cistromic and transcriptomic analyses to interrogate the relationship between GRHL2 and pS118-ER. We found that GRHL2 is bound to chromatin at pS118-ER/GRHL2 co-occupancy sites prior to ligand treatment, and GRHL2 binding is required for maximal pS118-ER recruitment. pS118-ER/GRHL2 co-occupancy sites were enriched at active enhancers marked by H3K27ac and H3K4me1, along with FOXA1 and p300. Transcriptomic analysis yielded four subsets of ER/GRHL2 co-regulated genes revealing that GRHL2 can both enhance and antagonize E2-mediated ER transcriptional activity. Gene ontology analysis identified several coregulated genes involved in cell migration. Accordingly, knockdown of GRHL2 combined with estrogen treatment resulted in increased cell migration but no change in proliferation. These results support a model in which GRHL2 binds to select enhancers and facilitates pS118-ER recruitment to chromatin which then results in differential activation and repression of genes that control ER-positive breast cancer cell migration.
2022-05-19 | GSE202621 | GEO
Project description:Phosphorylation of estrogen receptor α (ER) at serine 118 (pS118-ER) is induced by estrogen and is the most abundant post-translational mark associated with a transcriptionally active receptor. Cistromic analysis of pS118-ER from our group found enrichment of the GRHL2 motif near pS118-ER binding sites. In this report we use cistromic and transcriptomic analyses to interrogate the relationship between GRHL2 and pS118-ER. We found that GRHL2 is bound to chromatin at pS118-ER/GRHL2 co-occupancy sites prior to ligand treatment, and GRHL2 binding is required for maximal pS118-ER recruitment. pS118-ER/GRHL2 co-occupancy sites were enriched at active enhancers marked by H3K27ac and H3K4me1, along with FOXA1 and p300. Transcriptomic analysis yielded four subsets of ER/GRHL2 co-regulated genes revealing that GRHL2 can both enhance and antagonize E2-mediated ER transcriptional activity. Gene ontology analysis identified several coregulated genes involved in cell migration. Accordingly, knockdown of GRHL2 combined with estrogen treatment resulted in increased cell migration but no change in proliferation. These results support a model in which GRHL2 binds to select enhancers and facilitates pS118-ER recruitment to chromatin which then results in differential activation and repression of genes that control ER-positive breast cancer cell migration.
2022-05-19 | GSE202620 | GEO
Project description:Phosphorylation of estrogen receptor α (ER) at serine 118 (pS118-ER) is induced by estrogen and is the most abundant post-translational mark associated with a transcriptionally active receptor. Cistromic analysis of pS118-ER from our group found enrichment of the GRHL2 motif near pS118-ER binding sites. In this report we use cistromic and transcriptomic analyses to interrogate the relationship between GRHL2 and pS118-ER. We found that GRHL2 is bound to chromatin at pS118-ER/GRHL2 co-occupancy sites prior to ligand treatment, and GRHL2 binding is required for maximal pS118-ER recruitment. pS118-ER/GRHL2 co-occupancy sites were enriched at active enhancers marked by H3K27ac and H3K4me1, along with FOXA1 and p300. Transcriptomic analysis yielded four subsets of ER/GRHL2 co-regulated genes revealing that GRHL2 can both enhance and antagonize E2-mediated ER transcriptional activity. Gene ontology analysis identified several coregulated genes involved in cell migration. Accordingly, knockdown of GRHL2 combined with estrogen treatment resulted in increased cell migration but no change in proliferation. These results support a model in which GRHL2 binds to select enhancers and facilitates pS118-ER recruitment to chromatin which then results in differential activation and repression of genes that control ER-positive breast cancer cell migration.
2022-05-19 | GSE202619 | GEO
Project description:The Grainyhead family of transcription factors controls morphogenesis and differentiation of epithelial cell layers in multicellular organisms by regulating cell junction- and proliferation-related genes. Grainyhead-like 2 (Grhl2) is expressed in developing mouse lung epithelium and is required for normal lung organogenesis. The specific epithelial cells expressing Grhl2 and the genes regulated by Grhl2 in normal lungs are mostly unknown. In these studies, we identified the NK2 homeobox 1 transcription factor (Nkx2-1) as a direct transcriptional target of Grhl2. By binding and transcriptional assays, and by confocal microscopy we showed that these two transcription factors form a positive feed-back loop in vivo and in cell lines, and are co-expressed in lung bronchiolar and alveolar type II cells. The morphological changes observed in flattening lung alveolar type II cells in culture are associated with down-regulation of Grhl2 and Nkx2-1. Reduction of Grhl2 in lung epithelial cell lines results in lower expression levels of Nkx2-1 and of known Grhl2 target genes. By microarray analysis we identified that in addition to Cadherin1 and Claudin4, Grhl2 regulates other cell interaction genes such as semaphorins and their receptors, which also play a functional role in developing lung epithelium. Impaired collective cell migration observed in Grhl2 knockdown cell monolayers is associated with reduced expression of these genes and may contribute to the altered epithelial phenotype reported in Grhl2 mutant mice. Thus, Grhl2 functions at the nexus of a novel regulatory network, connecting lung epithelial cell identity, migration and cell-cell interactions. To identify genes regulated by GRHL2 in lung epithelial cells, we performed cDNA microarray analyses in MLE15 cells transduced with Grhl2-shRNA and compared to a non-silencing control. Independent transductions of MLE15 cells using Grhl2-shRNA (n=3) and a non-silencing control (n=2) were analyzed.
2012-09-10 | E-GEOD-40729 | biostudies-arrayexpress
Project description:Healthy placental development is essential for reproductive success; failure of the feto-maternal interface results in preeclampsia and intrauterine growth retardation. We found that grainyhead-like 2 (GRHL2), a CP2-type transcription factor, is highly expressed in chorionic trophoblast cells, including basal chorionic trophoblast (BCT) cells located at the chorioallantoic interface in murine placentas. Placentas from Grhl2-deficient mouse embryos displayed defects in BCT cell polarity and basement membrane integrity at the chorioallantoic interface, as well as a severe disruption of labyrinth branchingmorphogenesis.Selective Grhl2 inactivation only in epiblastderived cells rescued all placental defects but phenocopied intraembryonic defects observed in global Grhl2 deficiency, implying the importance of Grhl2 activity in trophectoderm-derived cells. ChIPseq identified 5282 GRHL2 binding sites in placental tissue. By integrating these data with placental gene expression profiles, we identified direct and indirect Grhl2 targets and found a marked enrichment of GRHL2 binding adjacent to genes downregulated in Grhl2−/− placentas, which encoded known regulators of placental development and epithelial morphogenesis. These genes included that encoding the serine protease inhibitor Kunitz type 1 (Spint1), which regulates BCT cell integrity and labyrinth formation. In human placenta, we found that human orthologs of murine GRHL2 and its targets displayed co-regulation and were expressed in trophoblast cells in a similar domain as in mouse placenta. Our data indicate that a conserved Grhl2-coordinated gene network controls trophoblast branching morphogenesis, thereby facilitating development of the site of feto-maternal exchange. This might have implications for syndromes related to placental dysfunction. In vivo genome-wide examination of binding sites of the transcription factor GRHL2 by ChIP-seq using wild-type murine E17.5 placenta tissue. Two samples in total: one GRHL2 ChIP sample and one IgG ChIP sample using wild-type placentas tissue as antibody control.
2015-03-10 | E-GEOD-65962 | biostudies-arrayexpress
Project description:Using a retrovirus-mediated cDNA expression cloning approach we identified the grainyhead-like 2 (GRHL2) transcription factor as novel protooncogene. Overexpression of GRHL2 in NIH3T3 cells induced striking morphological changes, an increase in cell proliferation, anchorage-independent growth, and tumor growth in vivo. By combining a microarray analysis and a phylogenetic footprinting analysis with various biochemical assays we identified the epidermal growth factor receptor family member Erbb3 as a novel GRHL2 target gene. In breast cancer cell lines, shRNA-mediated knockdown of GRHL2 expression or functional inactivation of GRHL2 using dominant-negative GRHL2 proteins induce downregulation of ERBB3 gene expression, a striking reduction in cell proliferation and morphological and phenotypical alterations characteristic of an epithelial-to-mesenchymal transition (EMT), thus implying dual roles of GRHL2 in breast carcinogenesis. Interestingly, we could further demonstrate that expression of GRHL2 is directly suppressed by the transcription factor zinc-finger-enhancer binding protein 1 (ZEB1) which in turn is a direct target for repression by GRHL2, suggesting that the EMT transcription factors GRHL2 and ZEB1 form a double negative regulatory feedback loop in breast cancer cells. Finally, a comprehensive immunohistochemical analysis of GRHL2 expression in primary breast cancers showed loss of GRHL2 expression at the invasive front of primary tumors. A pathophysiological relevance of GRHL2 in breast cancer metastasis is further demonstrated by our finding of a statistically significant association between loss of GRHL2 expression in primary breast cancers and lymph-node metastasis. We thus demonstrate a crucial role of GRHL2 in breast carcinogenesis. To evaluate the role of the GRHL2 transcription factor in carcinogenessis we overexpressed the human GRHL2 protein in NIH3T3 cells. Parental NIH3T3 cells do not express the orthologic protein. Alterations in genome-wide transcriptional profiles were determined by microarray analysis.
2013-09-05 | E-GEOD-43610 | biostudies-arrayexpress
Project description:Ovarian cancer (OC) cells exhibit varying extents of epithelial/mesenchymal phenotype, forming an EMT spectrum based on their EMT scores. Combining 450K DNA methylation array, ChIP-sequencing of five histone H3 marks (H3K4me1, H3K4me3, H3K27Ac, H3K27me3 and H3K9me3) and transcriptomic analyses, we examined the genome-wide epigenetic profiles of OC cell lines with progressive EMT phenotypes, including a knockdown model of EMT suppressor Grainyhead-like 2 (GRHL2) which showed intermediate state transition. We identified differentially methylated CpG sites (DMCs) associated with EMT genes, found mainly at the promoters of epithelial genes including CDH1, GRHL2 and genes with GRHL2 binding sites. This prompted us to further study the epigenetic role of GRHL2. GRHL2-knockdown resulted in CpG methylation gain at GRHL2 binding sites and at DMCs associated with epithelial genes. Importantly, the changes of histone modifications occurred in GRHL2-knockdown cells are also more prominent among epithelial genes and at GRHL2 binding sites—reduction in permissive marks H3K4me3 and H3K27ac; elevated repressive mark H3K27me3—similar to the transitions observed in a four-cell-line model representing the EMT spectrum. We tested the effects of GRHL2 overexpression in conjunction with epigenetic drugs 5-azacitidine, GSK126 and mocetinostat, all of which exerted MET effects to different extents, depending on the existing cell state. Overall, GRHL2 is required for the epigenetic and chromatin remodeling of epithelial genes during EMT/MET that control intermediate phenotype switching.
2019-08-06 | GSE118405 | GEO