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Series GSE113092 Query DataSets for GSE113092
Status Public on Apr 13, 2018
Title GRHL2 is a key lineage determining factor which collaborates with FOXA1 to establish a targetable collateral pathway in the setting of endocrine therapy-resistant breast cancer [ChIP-seq]
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary The estrogen receptor (ER) is expressed in the majority of luminal breast cancers and inhibition of its transcriptional activity with selective estrogen receptor modulators, selective estrogen receptor degraders and/or aromatase inhibitors is a standard approach used in the management of this disease. Despite the positive clinical impact of these interventions, de novo and acquired resistance limits the therapeutic lifespan of these classes of drugs. Considering what is known about the complex mechanisms that contribute to the development of resistance it is likely that further development of ER-modulators will yield only incremental improvements. Thus, with the view that resistance is inevitable, we undertook the development of a new approach to treat ER-positive breast cancer by identifying and exploiting targetable vulnerabilities that emerge in endocrine therapy resistant disease. Genomic discovery platforms, including DNASeq, ChIPSeq and RNASeq were used to assess the epigenome, targeting global transcription factor binding profile, and transcriptome in cellular models of endocrine therapy sensitive and resistant disease. DNASeq was first used to identify the chromatin state, with a focus on differences, between these two models. Motif enrichment analysis indicated FOXA1 was a candidate transcription factor influencing the chromatin architecture, which was consistent with previously published studies. This led to the examination of the FOXA1 chromatin binding profile in these models. FOXA1 has previously been described to bind at enhancers. Furthermore, the relative transcription activity of specific enhancers has been shown to be indicated by the epigenomic marks on histones flanking transcription factor binding sites. For this reason, we assessed the specific pattern of histone 3 lysine 4 methylation to confirm enhancer status and histone 3 lysine 27 acetylation as an indicator of transcriptional activity. The specific patterns and distribution of FOXA1 binding was then integrated with this epigenomic information to reveal a subset of enhancers that became activated and another subset that gained enhanced activation in the tamoxifen resistant setting relative to the tamoxifen sensitive model from which it was derived. These results were integrated with the differential transcriptome, or genes shown to be differential expressed based on RNASeq, in the TAMR model as compared to its parental cell line, MCF7-WS8, and confirmed that the active enhancers were in fact associated with genes that were expressed more highly, on average, in the TAMR model.  Motif enrichment at these two subgroups of enhancers indicated that another transcription factor, GRHL2, likely interacts with FOXA1 at these active sites. These results were again integrated with the “differential transcriptome” based on RNASeq and confirmed that the active enhancers, and indicated an even stronger enrichment of genes that were expressed more highly, on average, in the TAMR model relative to the MCF7-WS8 model. The GRHL2 transcriptome was then further defined by both GRHL2 ChIPSeq as well as RNASeq by comparing TAMR samples in which downregulation of GRHL2 expression had been achieved via siRNA as compared to control siRNA sequences. The collection of these data defined a subset of genes, the GRHL2 dependent transcriptome, that demonstrated increased expression in TAMR. The results of these cell lines studies were corroborated by assessing the transcriptome of xenograft mouse models of endocrine therapy sensitive and resistant disease. Integrative analysis of these data identified a collateral ER-independent signaling pathway in endocrine therapy resistant tumors that converges upon and modulates the FOXA1 and GRHL2 cistrome/transcriptome.
 
Overall design ChIP-Seq profiling of key factors in WS8 and TAMR cells. All samples have triplicate biological replicates.
 
Contributor(s) Jasper JS, Cocce KJ, Everett L, Wardell S, Westerling T, Krebs T, Baldi R, Wright TM, Yllanes A, Blitzer JT, Logsdon C, Rakiec D, Ruddy D, Hyslop T, Hall A, Marks JR, Crawford GE, Brown M, Mcdonnell DP
Citation(s) 31644911
Submission date Apr 12, 2018
Last update date Dec 03, 2019
Contact name Jeff Jasper
Organization name Duke University
Department Pharmacology and Cancer Biology
Lab McDonnell
Street address Box 3813
City Durham
State/province NC
ZIP/Postal code 27710
Country USA
 
Platforms (1)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (83)
GSM3096429 TAMR_4OHT_FOXA1_KC119_Rep2
GSM3096430 TAMR_4OHT_FOXA1_KC120_Rep3
GSM3096431 TAMR_4OHT_FOXA1_KC138_Rep1
This SubSeries is part of SuperSeries:
GSE106695 GRHL2 is a key lineage determining factor which collaborates with FOXA1 to establish a targetable collateral pathway in the setting of endocrine therapy-resistant breast cancer
Relations
BioProject PRJNA449958
SRA SRP139878

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SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE113092_RAW.tar 15.0 Gb (http)(custom) TAR (of BED, BW)
GSE113092_up_peaks_down_peaks.bed.tar.gz 7.4 Mb (ftp)(http) TAR
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Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

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