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Series GSE124225 Query DataSets for GSE124225
Status Public on Nov 13, 2019
Title ARID1A is a critical regulator of luminal identity and therapeutic response in oestrogen receptor-positive breast cancer (ChIP-Seq)
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary 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.
 
Overall design ChIP-seq assay was performed on MCF7 breast cancer cells expressing three distinct sgARID1As or two control sgRNAs in DMSO or fulvestrant treated cells
 
Contributor(s) Toska E, Chhangawala S, Kadoch C
Citation(s) 31932695
Submission date Dec 20, 2018
Last update date Jan 23, 2020
Contact name Sagar Chhangawala
E-mail(s) sagar.cornell@gmail.com
Organization name Weill Cornell Medical College
Department PBSB
Street address 1300 York Ave.
City New York
State/province NY
ZIP/Postal code 10065
Country USA
 
Platforms (1)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
Samples (24)
GSM3525996 ChIP-Seq Sample_DMSO_MCF7_Control_BAF155_1
GSM3525997 ChIP-Seq Sample_DMSO_MCF7_Control_BRG_1
GSM3525998 ChIP-Seq Sample_DMSO_MCF7_Control_Input_1
This SubSeries is part of SuperSeries:
GSE124228 ARID1A is a critical regulator of luminal identity and therapeutic response in oestrogen receptor-positive breast cancer
Relations
BioProject PRJNA511019
SRA SRP174128

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE124225_RAW.tar 4.0 Gb (http)(custom) TAR (of BW)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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