Homo sapiens
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| DRR165735_1.fastq.gz | Fastqsanger.gz | |||
| DRR165735_2.fastq.gz | Fastqsanger.gz | |||
| DRR165736_1.fastq.gz | Fastqsanger.gz | |||
| DRR165736_2.fastq.gz | Fastqsanger.gz | |||
| DRR165737_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 8 |
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Project description:Elucidation of chromatin interactions for hormone therapy- resistance of ER positive breast cancer
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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
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 | GSE118714 | GEO
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.
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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.
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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.
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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.
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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.
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