Identifying FOXA1-GR transcriptional targets in FOXA1-GR dependent NSCLC
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE203036 | GEO | 2022/05/16
REPOSITORIES: GEO
Similar Datasets
Project description:Identifying FOXA1-GR transcriptional targets in FOXA1-GR dependent NSCLC
| PRJNA838217 | ENA
Project description:The estrogen receptor (ER), glucocorticoid receptor (GR), and forkhead box protein 1 (FoxA1) are significant factors in breast cancer progression. FoxA1 is well-established as a pioneer factor for steroid receptor recruitment to chromatin. Here we show that ER and GR have the ability to alter the genomic response of FoxA1 to specific binding sites within the genome. These findings alter the classical understood mechanism of FoxA1 establishing a dynamic transcription factor that can be regulated by hormones.
2016-04-08 | GSE72249 | GEO
Project description:FOXA1 is a pioneer factor that is important in hormone dependent cancer cells to stabilise nuclear receptors, such as estrogen receptor (ER) to chromatin. FOXA1 binds to enhancers regions that are enriched in H3K4mono- and dimethylation (H3K4me1, H3K4me2) histone marks and evidence suggests that these marks are requisite events for FOXA1 to associate with enhancers to initate subsequent gene expression events. However, exogenous expression of FOXA1 has been shown to induce H3K4me1 and H3K4me2 signal at enhancer elements and the order of events and the functional importance of these events is not clear. We performed a FOXA1 Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins (RIME) screen in ERα-positive MCF-7 breast cancer cells in order to identify FOXA1 interacting partners and we found histone-lysine N-methyltransferase (MLL3) as the top FOXA1 interacting protein. MLL3 is typically thought to induce H3K4me3 at promoter regions, but recent findings suggest it may contribute to H3K4me1 deposition, in line with our observation that MLL3 associates with an enhancer specific protein. We performed MLL3 ChIP-seq in breast cancer cells and unexpectedly found that MLL3 binds mostly at non-promoter regions enhancers, in contrast to the prevailing hypothesis. MLL3 was shown to occupy regions marked by FOXA1 occupancy and as expected, H3K4me1 and H3K4me2. MLL3 binding was dependent on FOXA1, indicating that FOXA1 recruits MLL3 to chromatin. Motif analysis and subsequent genomic mapping revealed a role for Grainy head like protein-2 (GRHL2) which was shown to co-occupy regions of the chromatin with MLL3. Regions occupied by all three factors, namely FOXA1, MLL3 and GRHL2, were most enriched in H3K4me1. MLL3 silencing decreased H3K4me1 at enhancer elements, but had no appreciable impact on H3K4me3 at enhancer elements. We identify a complex relationship between FOXA1, MLL3 and H3K4me1 at enhancers in breast cancer and propose a mechanism whereby the pioneer factor FOXA1 can interact with a chromatin modifier MLL3, recruiting it to chromatin to facilitate the deposition of H3K4me1 histone marks, subsequently demarcating active enhancer elements.
2016-12-12 | PXD005253 | Pride
Project description:Treatment of prostate cancer relies predominantly on the inhibition of androgen receptor (AR) signaling. Despite the initial effectiveness of the AR-targeted therapies, the cancer often develops resistance to the AR blockade. One mechanism of the resistance is glucocorticoid receptor (GR)-mediated replacement of AR. Nevertheless, the mechanistic ways and means how the GR-mediated antiandrogen resistance occurs has remained elusive. Here, we have discovered several crucial features of GR action in prostate cancer cells through genome-wide techniques. We detected that the replacement of AR by GR in antiandrogen-exposed prostate cancer cells occurs almost exclusively at pre-accessible chromatin sites displaying FOXA1 occupancy. Counterintuitively to the classical pioneer factor model, silencing of FOXA1 potentiated the chromatin binding and transcriptional activity of GR. This was attributed to FOXA1-mediated repression of the NR3C1 (gene encoding GR) expression via the corepressor TLE3. In comparison to FOXA1, inhibition of coregulator activity efficiently restricted GR-mediated gene regulation and cell proliferation. Overall, we identified chromatin pre-accessibility and FOXA1-mediated repression as important regulators of GR action in prostate cancer, pointing out new avenues to oppose steroid receptor-mediated drug resistance.
2023-11-07 | GSE214756 | GEO
Project description:Treatment of prostate cancer relies predominantly on the inhibition of androgen receptor (AR) signaling. Despite the initial effectiveness of the AR-targeted therapies, the cancer often develops resistance to the AR blockade. One mechanism of the resistance is glucocorticoid receptor (GR)-mediated replacement of AR. Nevertheless, the mechanistic ways and means how the GR-mediated antiandrogen resistance occurs has remained elusive. Here, we have discovered several crucial features of GR action in prostate cancer cells through genome-wide techniques. We detected that the replacement of AR by GR in antiandrogen-exposed prostate cancer cells occurs almost exclusively at pre-accessible chromatin sites displaying FOXA1 occupancy. Counterintuitively to the classical pioneer factor model, silencing of FOXA1 potentiated the chromatin binding and transcriptional activity of GR. This was attributed to FOXA1-mediated repression of the NR3C1 (gene encoding GR) expression via the corepressor TLE3. In comparison to FOXA1, inhibition of coregulator activity efficiently restricted GR-mediated gene regulation and cell proliferation. Overall, we identified chromatin pre-accessibility and FOXA1-mediated repression as important regulators of GR action in prostate cancer, pointing out new avenues to oppose steroid receptor-mediated drug resistance.
2023-11-07 | GSE214754 | GEO
Project description:Treatment of prostate cancer relies predominantly on the inhibition of androgen receptor (AR) signaling. Despite the initial effectiveness of the AR-targeted therapies, the cancer often develops resistance to the AR blockade. One mechanism of the resistance is glucocorticoid receptor (GR)-mediated replacement of AR. Nevertheless, the mechanistic ways and means how the GR-mediated antiandrogen resistance occurs has remained elusive. Here, we have discovered several crucial features of GR action in prostate cancer cells through genome-wide techniques. We detected that the replacement of AR by GR in antiandrogen-exposed prostate cancer cells occurs almost exclusively at pre-accessible chromatin sites displaying FOXA1 occupancy. Counterintuitively to the classical pioneer factor model, silencing of FOXA1 potentiated the chromatin binding and transcriptional activity of GR. This was attributed to FOXA1-mediated repression of the NR3C1 (gene encoding GR) expression via the corepressor TLE3. In comparison to FOXA1, inhibition of coregulator activity efficiently restricted GR-mediated gene regulation and cell proliferation. Overall, we identified chromatin pre-accessibility and FOXA1-mediated repression as important regulators of GR action in prostate cancer, pointing out new avenues to oppose steroid receptor-mediated drug resistance.
2023-11-07 | GSE214753 | GEO
Project description:We report the dual role of FoxA1 in androgen receptor recruitment to the chromatin of androgen responsive prostate cancer cell line LNCaP-1F5 using ChIP-sequencing. Depletion of FoxA1 reprograms both androgen and glucocorticoid receptor recruitment and subsequent gene expression. The ChIP-seq has been performed using AR, FoxA1, GR, H3K4me2 antibodies. We have also mapped the DNaseI-hypersensitive sites (DHS) using deep sequencing. Examination of AR, FoxA1, GR, H3K4me2 binding sites and DHS sites in parental and FoxA1 depleted LNCaP-1F5 cells.
2011-09-14 | E-GEOD-30623 | biostudies-arrayexpress
Project description:Invasive Lobular Carcinoma (ILC) is the second most frequent breast cancer (BCa) type and encompasses 10-15% of BCa cases. FOXA1 specific mutations are enriched in this subtype of BCa, however their role in breast cancer pathogenesis is still ill-defined. FOXA1, together with estrogen receptor (ER), is a key transcription factor for the correct activation of estrogen-dependent gene expression and, consequently, for mammary gland development and BCa identity. FOXA1 has the capability to bind to and de-compact heterochromatin to render it accessible for other nuclear proteins, such as ER, and allow activation of their transcriptional programs upon estrogen stimulation. In this project, we aim to elucidate the role of FOXA1 missense mutations in altering its binding to DNA, chromatin accessibility, ER-dependent transcription and their implication in limiting the sensitivity to standard-of-care anti-hormonal therapy, commonly used in ER-positive BCa patients. To this end, we have generated BCa cell lines expressing these FOXA1 mutations and we will employ ATAC-Seq, RIME assays, ChIP-Seq and RNA-Seq to ascertain their effect on DNA accessibility, DNA binding capability, as well as binding of transcriptional coregulators, such as ER, to chromatin. We will extend our analyses to our internal BCa patient datasets with detailed clinical annotation to study the correlation between presence of FOXA1 mutations and response to anti-hormonal therapy of ER-positive BCa patients. The results of this project will allow to understand how the different mutations in the Forkhead domain can alter FOXA1 and ER function, transcriptional regulation and response to anti-hormonal therapy in ER-positive BCa patients.
2020-11-19 | GSE161767 | GEO
Project description:Invasive Lobular Carcinoma (ILC) is the second most frequent breast cancer (BCa) type and encompasses 10-15% of BCa cases. FOXA1 specific mutations are enriched in this subtype of BCa, however their role in breast cancer pathogenesis is still ill-defined. FOXA1, together with estrogen receptor (ER), is a key transcription factor for the correct activation of estrogen-dependent gene expression and, consequently, for mammary gland development and BCa identity. FOXA1 has the capability to bind to and de-compact heterochromatin to render it accessible for other nuclear proteins, such as ER, and allow activation of their transcriptional programs upon estrogen stimulation. In this project, we aim to elucidate the role of FOXA1 missense mutations in altering its binding to DNA, chromatin accessibility, ER-dependent transcription and their implication in limiting the sensitivity to standard-of-care anti-hormonal therapy, commonly used in ER-positive BCa patients. To this end, we have generated BCa cell lines expressing these FOXA1 mutations and we will employ ATAC-Seq, RIME assays, ChIP-Seq and RNA-Seq to ascertain their effect on DNA accessibility, DNA binding capability, as well as binding of transcriptional coregulators, such as ER, to chromatin. We will extend our analyses to our internal BCa patient datasets with detailed clinical annotation to study the correlation between presence of FOXA1 mutations and response to anti-hormonal therapy of ER-positive BCa patients. The results of this project will allow to understand how the different mutations in the Forkhead domain can alter FOXA1 and ER function, transcriptional regulation and response to anti-hormonal therapy in ER-positive BCa patients.
2020-11-19 | GSE134655 | GEO
Project description:Invasive Lobular Carcinoma (ILC) is the second most frequent breast cancer (BCa) type and encompasses 10-15% of BCa cases. FOXA1 specific mutations are enriched in this subtype of BCa, however their role in breast cancer pathogenesis is still ill-defined. FOXA1, together with estrogen receptor (ER), is a key transcription factor for the correct activation of estrogen-dependent gene expression and, consequently, for mammary gland development and BCa identity. FOXA1 has the capability to bind to and de-compact heterochromatin to render it accessible for other nuclear proteins, such as ER, and allow activation of their transcriptional programs upon estrogen stimulation. In this project, we aim to elucidate the role of FOXA1 missense mutations in altering its binding to DNA, chromatin accessibility, ER-dependent transcription and their implication in limiting the sensitivity to standard-of-care anti-hormonal therapy, commonly used in ER-positive BCa patients. To this end, we have generated BCa cell lines expressing these FOXA1 mutations and we will employ ATAC-Seq, RIME assays, ChIP-Seq and RNA-Seq to ascertain their effect on DNA accessibility, DNA binding capability, as well as binding of transcriptional coregulators, such as ER, to chromatin. We will extend our analyses to our internal BCa patient datasets with detailed clinical annotation to study the correlation between presence of FOXA1 mutations and response to anti-hormonal therapy of ER-positive BCa patients. The results of this project will allow to understand how the different mutations in the Forkhead domain can alter FOXA1 and ER function, transcriptional regulation and response to anti-hormonal therapy in ER-positive BCa patients.
2020-11-19 | GSE134654 | GEO