Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Epigenetic reprogramming at estrogen-receptor binding sites alters the 3D chromatin landscape in endocrine resistant breast cancer [ChIP-seq]

ABSTRACT: Endocrine therapy resistance invariably develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown. Here, we show that 3-dimensional (3D) chromatin interactions both within and between topologically associating domains (TADs) frequently change in ER+ endocrine resistant breast cancer cells and that the differential interactions are enriched for genetic variants at CTCF-bound anchors. Ectopic chromatin interactions are preferentially enriched at active enhancers and promoters and ER binding sites and are associated with altered expression of ER-regulated genes, consistent with dynamic remodelling of ER pathways accompanying the development of endocrine resistance. Importantly, new 3D chromatin interactions often occur coincidently with hypermethylation and loss of ER binding. Additionally, alterations in active (A-type) and inactive (B-type) chromosomal compartments are also associated with decreased ER binding and atypical interactions and gene expression. Together, our results suggest that 3D epigenome remodelling is a key mechanism underlying endocrine resistance in ER+ breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118711 | GEO | 2019/12/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Epigenetic reprogramming at estrogen-receptor binding sites alters the 3D chromatin landscape in endocrine resistant breast cancer [WGS]

Project description:Endocrine therapy resistance invariably develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown. Here, we show that 3-dimensional (3D) chromatin interactions both within and between topologically associating domains (TADs) frequently change in ER+ endocrine resistant breast cancer cells and that the differential interactions are enriched for genetic variants at CTCF-bound anchors. Ectopic chromatin interactions are preferentially enriched at active enhancers and promoters and ER binding sites and are associated with altered expression of ER-regulated genes, consistent with dynamic remodelling of ER pathways accompanying the development of endocrine resistance. Importantly, new 3D chromatin interactions often occur coincidently with hypermethylation and loss of ER binding. Additionally, alterations in active (A-type) and inactive (B-type) chromosomal compartments are also associated with decreased ER binding and atypical interactions and gene expression. Together, our results suggest that 3D epigenome remodelling is a key mechanism underlying endocrine resistance in ER+ breast cancer.

2019-12-11 | GSE118715 | GEO

Epigenetic reprogramming at estrogen-receptor binding sites alters the 3D chromatin landscape in endocrine resistant breast cancer [WGBS]

2019-12-11 | GSE118714 | GEO

Epigenetic reprogramming at estrogen-receptor binding sites alters the 3D chromatin landscape in endocrine resistant breast cancer [RNA-seq]

2019-12-11 | GSE118713 | GEO

Epigenetic reprogramming at estrogen-receptor binding sites alters the 3D chromatin landscape in endocrine resistant breast cancer [Hi-C]

2019-12-11 | GSE118712 | GEO

Deregulation of the three-dimensional epigenome in endocrine resistant breast cancer

Project description:Around 35% of Estrogen Receptor (ER) positive patients develop resistance and relapse, highlighting the need to further understand the mechanisms underpinning endocrine resistance in breast cancer. Here, we study 3-dimensional (3D) epigenome remodelling in endocrine resistant breast cancer cells. We show that chromatin interactions both within and between topologically associating domains (TADs) frequently change in resistant breast cancer cells and that alterations in active (A-type) and inactive (B-type) chromosomal compartments are associated with decreased ER binding and atypical interactions and gene expression. Finally, we identify differentially interacting ER-bound regions that preferentially connect active enhancers and promoters associated with altered expression of ER-regulated genes. Importantly, interactions specifically associated with endocrine resistance, often occur coincidently with hypermethylation of ER binding. Our results demonstrate that 3D epigenome remodelling is a key mechanism of endocrine resistance that consists of differential chromatin interactions and aberrant DNA methylation at ER-regulated enhancer regions.

2019-12-11 | GSE130916 | GEO

FoxA1 is a critical determinant of Estrogen Receptor function and endocrine response (part II)

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

FoxA1 is a critical determinant of Estrogen Receptor function and endocrine response (part I)

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

ARID1A is a critical regulator of luminal identity and therapeutic response in oestrogen receptor-positive breast cancer (ChIP-seq II)

Project description:Mutations in ARID1A, a subunit of the SWI/SNF chromatin remodelling complex, are the most common somatic alteration of the SWI/SNF complex across all cancers including oestrogen receptor positive (ER)+ breast cancer. We have recently reported that ARID1A inactivating mutations are present at a high frequency in advanced endocrine resistant ER+ breast cancer. In parallel, to identify mechanisms of resistance to endocrine therapy in breast cancer, we performed an epigenome CRISPR/CAS9 knockout screen that identified ARID1A as the top candidate whose loss determines resistance to the ER degrader fulvestrant. ARID1A knockout cells were found to be less responsive to endocrine therapy compared to intact ARID1A cells in vitro and in vivo. This set of observations in patients’ tumours and in unbiased CRISPR screens led us to explore the epigenetic mechanisms whereby loss of ARID1A may influence breast cancer progression and/or endocrine therapy resistance. ARID1A disruption in ER+ breast cancer cells led to widespread changes in chromatin accessibility converging on loss of the master transcription factors (TFs) that regulate gene expression programs critical for luminal lineage identity. Global transcriptome profiling of ARID1A knockout cell lines and patient samples harbouring ARID1A inactivating mutations revealed an enrichment for basal-like gene expression signatures. The state of increased cellular plasticity of luminal cells that acquire a basal-like phenotype upon ARID1A inactivation is enabled by loss of ARID1A-dependent SWI/SNF complex targeting to genomic sites of the major luminal-lineage determining transcription factors including ER, FOXA1, and GATA3. We also show that ARID1A regulates genome-wide ER-chromatin interactions and ER-dependent transcription. Altogether, we uncover a critical role for ARID1A in the determination of breast luminal cell identity and endocrine therapeutic response in ER+ breast cancer.

2019-11-13 | GSE140185 | GEO

ARID1A is a critical regulator of luminal identity and therapeutic response in oestrogen receptor-positive breast cancer (RNA-Seq)

2019-11-13 | GSE124227 | GEO

ARID1A is a critical regulator of luminal identity and therapeutic response in oestrogen receptor-positive breast cancer (ChIP-Seq)

2019-11-13 | GSE124225 | GEO