Identification of overlap between KDM3A and FOXA1 regulated transcriptome in the ER positive breast cancer cell line MCF-7
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE124270 | GEO | 2019/08/07
REPOSITORIES: GEO
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Project description:Using a siRNA screen we identified the histone demethylase enzyme KDM3A as a potential positive regulator of ER signalling in breast cancer. To interrogate the full extent of KDM3A regulation on ER signalling we assessed basal and estrogen (E2)- stimulated global gene expression changes in KDM3A-depleted MCF-7 cells by microarray analysis using the Illumina Human HT12 Version 4 BeadChip array. We identified ER regulated genes affected by KDM3A knockdown and determined that KDM3A is required for ER recruitment to estrogen response elements in the promotors of ER regulated genes. We also identified that KDM3A regulates expression of a number of genes involved in proliferation and that knockdown of KDM3A inhibits ER positive breast cancer cell growth.
2015-05-16 | GSE68918 | GEO
Project description:Using a siRNA screen we identified the histone demethylase enzyme KDM3A as a potential positive regulator of ER signalling in breast cancer. To interrogate the full extent of KDM3A regulation on ER signalling we assessed basal and estrogen (E2)- stimulated global gene expression changes in KDM3A-depleted MCF-7 cells by microarray analysis using the Illumina Human HT12 Version 4 BeadChip array. We identified ER regulated genes affected by KDM3A knockdown and determined that KDM3A is required for ER recruitment to estrogen response elements in the promotors of ER regulated genes. We also identified that KDM3A regulates expression of a number of genes involved in proliferation and that knockdown of KDM3A inhibits ER positive breast cancer cell growth. MCF-7 cells were transfected with either a non-silencing scrambled control siRNA (siSCR) or a KDM3A targeting siRNA (siKDM3A-B) using Lipfectamine RNAiMAX (Invitrogen) to a final concentration of 25 nM in steroid depleted conditions. Cells were grown for 48 hours prior to treatment with vehicle or 10 nM E2 for 4 hours before RNA extraction using TRIzol (Ambion, Life Technologies) and hybridization of triplicate samples to an Illumine HT-12 v4 BeadChip array. One sample failed due to low amounts of cRNA and was therefore not included in the analysis (siKDM3A + E2 Replicate 3). The array for replicates 1 and 2 was performed in August 2013 (Array 1) and replicate 3 in August 2014 (Array 2). When processing the data Array 2 was normalized to Array 1.
2015-05-16 | E-GEOD-68918 | biostudies-arrayexpress
Project description:To elucidate the KDM4B regulated transcriptomes in ER-positive breast cancer cells we assessed global gene expression changes in KDM4B-depleted MCF-7 cells by microarray analysis using the Illumina Human HT12 Version 4 BeadChip array. Differentially expressed genes were compared with KDM3A and FOXA1 regulated transcriptomes. We identified 229 genes co-regulated by all three enzymes and that co-regulated genes were involved in cell cycle processes. We identified that 53% and 48% of KDM4B-regulated genes were also regulated by KDM3A and FOXA1, with co-regulatory gene signatures being involved with estrogen response signatures and cell proliferation. We also identified that depletion of KDM3A and KDM4B together inhibits ER-target gene expression and ER-positive breast cancer cell growth more than depletion of either gene on its own.
2019-08-06 | GSE135427 | GEO
Project description:Identification of overlap between KDM3A and FOXA1 regulated transcriptome in the ER positive breast cancer cell line MCF-7
| PRJNA511446 | ENA
Project description:Cilia are dynamic antennae that sense the extracellular environment adjusting their length to maintain homeostasis. Mutant mouse models for the lysine demethylase KDM3A (JMJD1A, JMHD2A) share phenotypic features with human ciliopathies, including obesity and metabolic syndrome. Here we show that cilia of Kdm3a mutants are unstable with dysregulated length ranges accumulating intraflagellar transport proteins (IFTs) at the ciliary tip. RNA sequencing and mass-spectrometry identified actin cytoskeleton as the most miss-regulated feature during the ciliary cycle of KDM3A null cells and revealed that IFT81 contains Nε-methylated lysines in vivo to which recombinant KDM3A binds without subsequent demethylation. Mutations in these IFT81 methyl-lysine residues however stabilize KDM3A null cilia and potentiate ciliogenesis surpassing wild type cells; a synergism phenocopied by wild type cultures through the simultaneous destabilization of the actin cytoskeleton when over-expressing IFT81 lysine-mutants. Our work reveals that ciliogenesis requires the coordinated release of cytoskeletal constrains and the presence of intraflagellar transport proteins which KDM3A integrates aided by post-translationally modifiable lysine residues in IFT81.
2018-07-11 | PXD004334 | Pride
Project description:Estrogen Receptor-a (ER) is the key feature in the majority of breast cancers and ER binding to the genome correlates with the Forkhead protein FOXA1 (HNF3a), but mechanistic insight is lacking. We now show that FOXA1 is the defining factor that governs differential ER-chromatin interactions. We show that almost all ER-chromatin interactions and gene expression changes are dependent on the presence of FOXA1 and that FOXA1 dictates genome-wide chromatin accessibility. Furthermore, we show that CTCF is an upstream negative regulator of FOXA1-chromatin interactions. In ER responsive breast cancer cells, the dependency on FOXA1 for tamoxifen-ER activity is absolute and in tamoxifen resistant cells, ER binding occurs independently of ligand, but in a FOXA1 dependent manner. Importantly, expression of FOXA1 in non-breast cancer cells is sufficient to alter ER binding and response to endocrine treatment. As such, FOXA1 is the primary determinant that regulates estrogen-ER activity and endocrine response in breast cancer cells and is sufficient to program ER functionality in non-breast cancer contexts. FoxA1 silenced breast cancer MCF-7 cell lines or control siRNA in the presence of Estrogen or a vehicle. MCF-7 cells were hormone-depleted for 3 d and treated with 100 nM estrogen for 6 h. There were three biological replicates for each of the four different groups.
2010-11-17 | E-GEOD-25315 | biostudies-arrayexpress
Project description:Estrogen Receptor-a (ER) is the key feature in the majority of breast cancers and ER binding to the genome correlates with the Forkhead protein FOXA1 (HNF3a), but mechanistic insight is lacking. We now show that FOXA1 is the defining factor that governs differential ER-chromatin interactions. We show that almost all ER-chromatin interactions and gene expression changes are dependent on the presence of FOXA1 and that FOXA1 dictates genome-wide chromatin accessibility. Furthermore, we show that CTCF is an upstream negative regulator of FOXA1-chromatin interactions. In ER responsive breast cancer cells, the dependency on FOXA1 for tamoxifen-ER activity is absolute and in tamoxifen resistant cells, ER binding occurs independently of ligand, but in a FOXA1 dependent manner. Importantly, expression of FOXA1 in non-breast cancer cells is sufficient to alter ER binding and response to endocrine treatment. As such, FOXA1 is the primary determinant that regulates estrogen-ER activity and endocrine response in breast cancer cells and is sufficient to program ER functionality in non-breast cancer contexts. breast cancer MCF-7 cell lines were treaated in the presence of Estrogen, Estrogen plus Tamoxifen, Tamoxifen or a vehicle. MCF-7 cells were hormone-depleted for 3 d and treated with 100 nM estrogen or 1 microM Tamoxifen for 6 h. There were four biological replicates for each of the four different groups.
2010-11-17 | E-GEOD-25314 | biostudies-arrayexpress
Project description:The FOXA1 pioneer factor is an essential mediator of steroid receptor function in multiple hormone dependent cancers, including breast and prostate cancers, enabling nuclear receptors such as ER and AR to activate lineage specific growth programs. . Analyzing data from loss-of-function screens, we identified a subset of NSCLC tumor lines where proliferation is FOXA1-dependent. Using rapid immunoprecipitation and mass spectrometry of endogenous protein (RIME) we identified chromatin-localized interaction between FOXA1 and glucocorticoid receptor (GR) in these tumor cells. Knockdown of GR inhibited proliferation of FOXA1-dependent, but not FOXA1-independent NSCLC cells. Here, we utilized ChIP-sequencing to identify a permissive set of genes potentially regulated by FOXA1 and GR to understand potential mechanisms underlying FOXA1-GR dependence in NSCLC.
2022-05-16 | GSE203036 | GEO
Project description:Histone demethylation has important roles in regulating gene expression and forms part of the epigenetic memory system that regulates cell fate and identity, by still poorly understood mechanisms. Here we examined the role played by the histone demethylase Kdm3a, which demethylates lysine 9 of histone H3, during cellular differentiation. Using F9 mouse embryonal carcinoma cells as a model for progression through terminal differentiation, we showed that Kdm3a is essential to differentiation into parietal endoderm-like (PE) cells. On gene expression microarrays, we found several genes whose expression is upregulated by Kdm3a during endoderm differentiation, including the three developmental master players Dab2, Pdlim4, and FoxQ1. The role of Kdm3a as a transcriptional activator of these genes was correlated with its effect by demethylating dimethyl-lysine 9 of histone H3 (H3K9me2) at their promoters. We further demonstrated that Dab2 depletion, like Kdm3a depletion, prevents F9 cells from fully differentiating into PE cells. Nevertheless, the only overexpression of Dab2 in Kdm3a-depleted cells is not sufficient to completely restore the PE differentiation in Kdm3a-knockdown cells. Overall, our findings reveal that Kdm3a is crucial for progression through terminal differentiation, likely by regulating the expression of a set of master players in endoderm differentiation. The emergence of Kdm3a as a key modulator of cell fate decision strengthens the notion that histone demethylases are at the nexus of cell differentiation and development.
2012-06-15 | GSE33841 | GEO
Project description:Breast cancer invasive growth, metastasis and therapeutic resistance affects the clinical ourcome. We explored the epigenetic mechanisms that control these process in breast cancer cell line, MDA-MB-231 by knocking down a lysine specific demethylase KDM3A We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during this process. Human breast cancer cell line MDA-MB-231 was infected with scramble or KDM3A shRNA. After selection, the cells were used for microarray analysis.
2016-06-29 | E-GEOD-83818 | biostudies-arrayexpress