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| Status |
Public on Aug 15, 2023 |
| Title |
HOTAIRM1 suppresses Estrogen Receptor activity in breast cancer by restricting chromatin accessibility of pioneer factor FOXA1 |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Although a majority of breast cancers (BrCa) are Estrogen receptor-alpha (ERa)-positive, existing endocrine therapies that target ERa can lead to hormone-resistant disease. The mechanisms of how normal breast epithelium is transformed into malignant remain poorly defined, and a deeper understanding is needed to design novel therapeutics. Several epigenetic regulators including long non-coding RNAs (lncRNAs) are aberrantly expressed in BrCa, resulting in abnormal gene expression patterns and tumor growth. Here, we show that HOTAIRM1, which we previously defined as a p53-regulated lncRNA in human stem cells, acts as a tumor suppressor to counteract ERa-activity in BrCa. Global expression analyses uncovered a significant correlation between reduced HOTAIRM1 expression and poor survival of ER+ BrCa patients. Promoter DNA methylation and histone mark enrichment revealed that HOTAIRM1 is epigenetically silenced in BrCa patients and cell lines. We found that HOTAIRM1 depletion promotes, whereas exogenous HOTAIRM1 reduces survival and proliferation of BrCa cells. Guilt by association analysis in BrCa patients, combined with HOTAIRM1-dependent transcriptome profiling in BrCa cells reveal that HOTAIRM1 expression negatively correlates with proteins involved in ERa-activity and estrogen response. An unbiased profiling of HOTAIRM1-interactome show that HOTAIRM1 interacts with pioneer factor FOXA1 in ER+ BrCa cells. Further, our global ER/FOXA1 chromatin enrichment profiling in response to estrogen demonstrate increased enrichment of ER and FOXA1 to estrogen response elements (EREs) that results in significantly higher expression of ERa-targets in absence of HOTAIRM1. Thus, HOTAIRM1 suppresses ERa-activity in BrCa by restricting chromatin accessibility of pioneer factor FOXA1. To our knowledge, our results are the first to define a non-proteomic component that disrupts the activity of a pioneer factor in order to achieve tumor suppression
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| Overall design |
mRNA-Seq from siControl and siHOTAIRM1 MCF7 cells; ChIP-Seq of ER-alpha and FOXA1 in shControl and shHOTAIRM1 MCF7 cells deprived of hormones (-E2) or treated with Estrogen (+E2) for 1 hr
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| Contributor(s) |
Shi J, Jain A, Barton M |
| Citation missing |
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| Submission date |
Aug 16, 2019 |
| Last update date |
Aug 15, 2023 |
| Contact name |
Jiejun Shi |
| E-mail(s) |
jiejuns@uci.edu
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| Organization name |
University of California Irvine
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| Department |
School of Medicine
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| Lab |
Li lab
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| Street address |
5270 California Ave
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| City |
Irvine |
| State/province |
CA |
| ZIP/Postal code |
92617 |
| Country |
USA |
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| Platforms (1) |
| GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
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| Samples (18)
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| GSM4037336 |
MCF7 cells, siHOTAIRM1_rep1 RNA-seq |
| GSM4037337 |
MCF7 cells, siHOTAIRM1_rep2 RNA-seq |
| GSM4037338 |
MCF7 cells, siHOTAIRM1_rep3 RNA-seq |
| GSM4037339 |
MCF7 cells, shCtrl_-E2_ERalpha_ChIP-seq |
| GSM4037340 |
MCF7 cells, shCtrl_+E2_ERalpha_ChIP-seq |
| GSM4037341 |
MCF7 cells, shCtrl_-E2_FOXA1_ChIP-seq |
| GSM4037342 |
MCF7 cells, shCtrl_+E2_FOXA1_ChIP-seq |
| GSM4037343 |
MCF7 cells, shCtrl_-E2_Input_ChIP-seq |
| GSM4037344 |
MCF7 cells, shCtrl_+E2_Input_ChIP-seq |
| GSM4037345 |
MCF7 cells, shHot_-E2_ERalpha_ChIP-seq |
| GSM4037346 |
MCF7 cells, shHot_+E2_ERalpha_ChIP-seq |
| GSM4037347 |
MCF7 cells, shHot_-E2_FOXA1_ChIP-seq |
| GSM4037348 |
MCF7 cells, shHot_+E2_FOXA1_ChIP-seq |
| GSM4037349 |
MCF7 cells, shHot_-E2_Input_ChIP-seq |
| GSM4037350 |
MCF7 cells, shHot_+E2_Input_ChIP-seq |
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| Relations |
| BioProject |
PRJNA560493 |
| SRA |
SRP218544 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE135894_AllGene_FPKM_siHOTAIRM1_vs_siControl.tsv.gz |
599.7 Kb |
(ftp)(http) |
TSV |
| GSE135894_RAW.tar |
5.1 Gb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Processed data are available on Series record |
| Processed data provided as supplementary file |
| Raw data are available in SRA |
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