An integrative transcriptomics approach identifies miR-503 as a candidate master regulator of the estrogen response
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE78169 | GEO | 2016/08/19
SECONDARY ACCESSION(S): PRJNA312816
REPOSITORIES: GEO
Similar Datasets
Project description:Estrogen receptor α (ERα) is an important biomarker of breast cancer severity and a common therapeutic target. In response to estrogen, ERα stimulates a dynamic transcriptional program including both coding and noncoding RNAs. We generate a fine-scale map of expression dynamics by performing a temporal profiling of both messenger RNAs (mRNAs) and microRNAs (miRNAs) in MCF-7 cells (an ER+ model cell line for breast cancer) in response to estrogen stimulation. We identified three primary expression trends-transient, induced, and repressed-that were each enriched for genes with distinct cellular functions. Integrative analysis of mRNA and miRNA temporal expression profiles identified miR-503 as the strongest candidate master regulator of the estrogen response, in part through suppression of ZNF217-an oncogene that is frequently amplified in cancer. We confirmed experimentally that miR-503 directly targets ZNF217 and that overexpression of miR-503 suppresses MCF-7 cell proliferation. Moreover, the levels of ZNF217 and miR-503 are associated with opposite outcomes in breast cancer patient cohorts, with high expression of ZNF217 associated with poor survival and high expression of miR-503 associated with improved survival. Overall, these data indicate that miR-503 acts as a potent estrogen-induced candidate tumor suppressor miRNA that opposes cellular proliferation and has promise as a novel therapeutic for breast cancer. More generally, our work provides a systems-level framework for identifying functional interactions that shape the temporal dynamics of gene expression.
| S-EPMC5029456 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-08-19 | E-GEOD-78169 | biostudies-arrayexpress
Project description:Estrogen receptor α (ERα) is an important biomarker of breast cancer severity and a common therapeutic target. Recent studies have demonstrated that in addition to its role in promoting proliferation, ERα also protects tumors against metastatic transformation. Current therapeutics antagonize ERα and interfere with both beneficial and detrimental signaling pathways stimulated by ERα. The goal of this study is to uncover the dynamics of coding and non-coding RNA (microRNA) expression in response to estrogen stimulation and identify potential therapeutic targets that more specifically inhibit ERα-stimulated growth and survival pathways without interfering with its protective features. To achieve this, we exposed MCF7 cells (an estrogen receptor positive model cell line for breast cancer) to estrogen and prepared a time course of paired mRNA and miRNA sequencing libraries at ten time points throughout the first 24 hours of the response to estrogen. From these data, we identified three primary expression trendsâ??transient, induced, and repressedâ??that were each enriched for genes with distinct cellular functions. Integrative analysis of paired mRNA and microRNA temporal expression profiles identified miR-503 as the strongest candidate master regulator of the estrogen response, in part through suppression of ZNF217â??an oncogene that is frequently amplified in cancer. We confirmed experimentally that miR-503 directly targets ZNF217 and that over-expression of miR-503 suppresses breast cancer cell proliferation. Overall, these data indicate that miR-503 acts as a potent estrogen-induced tumor suppressor microRNA that opposes cellular proliferation and has promise as a therapeutic for breast cancer. More generally, our work provides a systems-level framework for identifying functional interactions that shape the temporal dynamics of gene expression. Quantification of miRNAs in MCF7 cells responding to estrogen following a period of estrogen starvation. Three independent biological replicates (30 samples: 3 replicates x 10 time points) of MCF7 cells were exposed to 10nM Estradiol for 0, 1, 2, 3, 4, 5, 6, 8, 12 , or 24 hours, and total RNA was extracted from the samples. Total RNA was used to generate paired RNA and miRNA sequencing. The miRNA libraries were prepared using the Bioo Scientific NextFLEX v2 library preparation kit.
2016-08-19 | E-GEOD-78168 | biostudies-arrayexpress
Project description:Estrogen receptor α (ERα) is an important biomarker of breast cancer severity and a common therapeutic target. Recent studies have demonstrated that in addition to its role in promoting proliferation, ERα also protects tumors against metastatic transformation. Current therapeutics antagonize ERα and interfere with both beneficial and detrimental signaling pathways stimulated by ERα. The goal of this study is to uncover the dynamics of coding and non-coding RNA (microRNA) expression in response to estrogen stimulation and identify potential therapeutic targets that more specifically inhibit ERα-stimulated growth and survival pathways without interfering with its protective features. To achieve this, we exposed MCF7 cells (an estrogen receptor positive model cell line for breast cancer) to estrogen and prepared a time course of paired mRNA and miRNA sequencing libraries at ten time points throughout the first 24 hours of the response to estrogen. From these data, we identified three primary expression trendsâ??transient, induced, and repressedâ??that were each enriched for genes with distinct cellular functions. Integrative analysis of paired mRNA and microRNA temporal expression profiles identified miR-503 as the strongest candidate master regulator of the estrogen response, in part through suppression of ZNF217â??an oncogene that is frequently amplified in cancer. We confirmed experimentally that miR-503 directly targets ZNF217 and that over-expression of miR-503 suppresses breast cancer cell proliferation. Overall, these data indicate that miR-503 acts as a potent estrogen-induced tumor suppressor microRNA that opposes cellular proliferation and has promise as a therapeutic for breast cancer. More generally, our work provides a systems-level framework for identifying functional interactions that shape the temporal dynamics of gene expression. Quantification of mRNAs in MCF7 cells responding to estrogen following a period of estrogen starvation. Three independent biological replicates (30 samples: 3 replicates x 10 time points) of MCF7 cells were exposed to 10nM Estradiol for 0, 1, 2, 3, 4, 5, 6, 8, 12 , or 24 hours, and total RNA was extracted from the samples. Total RNA was used to generate paired RNA and miRNA sequencing. RNA libraries were prepared using an Illumina TruSeq stranded mRNA library preparation kit.
2016-08-19 | E-GEOD-78167 | biostudies-arrayexpress
Project description:Estrogen receptor α (ERα) is an important biomarker of breast cancer severity and a common therapeutic target. Recent studies have demonstrated that in addition to its role in promoting proliferation, ERα also protects tumors against metastatic transformation. Current therapeutics antagonize ERα and interfere with both beneficial and detrimental signaling pathways stimulated by ERα. The goal of this study is to uncover the dynamics of coding and non-coding RNA (microRNA) expression in response to estrogen stimulation and identify potential therapeutic targets that more specifically inhibit ERα-stimulated growth and survival pathways without interfering with its protective features. To achieve this, we exposed MCF7 cells (an estrogen receptor positive model cell line for breast cancer) to estrogen and prepared a time course of paired mRNA and miRNA sequencing libraries at ten time points throughout the first 24 hours of the response to estrogen. From these data, we identified three primary expression trends—transient, induced, and repressed—that were each enriched for genes with distinct cellular functions. Integrative analysis of paired mRNA and microRNA temporal expression profiles identified miR-503 as the strongest candidate master regulator of the estrogen response, in part through suppression of ZNF217—an oncogene that is frequently amplified in cancer. We confirmed experimentally that miR-503 directly targets ZNF217 and that over-expression of miR-503 suppresses breast cancer cell proliferation. Overall, these data indicate that miR-503 acts as a potent estrogen-induced tumor suppressor microRNA that opposes cellular proliferation and has promise as a therapeutic for breast cancer. More generally, our work provides a systems-level framework for identifying functional interactions that shape the temporal dynamics of gene expression.
2016-08-19 | GSE78168 | GEO
Project description:Estrogen receptor α (ERα) is an important biomarker of breast cancer severity and a common therapeutic target. Recent studies have demonstrated that in addition to its role in promoting proliferation, ERα also protects tumors against metastatic transformation. Current therapeutics antagonize ERα and interfere with both beneficial and detrimental signaling pathways stimulated by ERα. The goal of this study is to uncover the dynamics of coding and non-coding RNA (microRNA) expression in response to estrogen stimulation and identify potential therapeutic targets that more specifically inhibit ERα-stimulated growth and survival pathways without interfering with its protective features. To achieve this, we exposed MCF7 cells (an estrogen receptor positive model cell line for breast cancer) to estrogen and prepared a time course of paired mRNA and miRNA sequencing libraries at ten time points throughout the first 24 hours of the response to estrogen. From these data, we identified three primary expression trends—transient, induced, and repressed—that were each enriched for genes with distinct cellular functions. Integrative analysis of paired mRNA and microRNA temporal expression profiles identified miR-503 as the strongest candidate master regulator of the estrogen response, in part through suppression of ZNF217—an oncogene that is frequently amplified in cancer. We confirmed experimentally that miR-503 directly targets ZNF217 and that over-expression of miR-503 suppresses breast cancer cell proliferation. Overall, these data indicate that miR-503 acts as a potent estrogen-induced tumor suppressor microRNA that opposes cellular proliferation and has promise as a therapeutic for breast cancer. More generally, our work provides a systems-level framework for identifying functional interactions that shape the temporal dynamics of gene expression.
2016-08-19 | GSE78167 | GEO
Project description:An integrative transcriptomics approach identifies miR-503 as a candidate master regulator of the estrogen response
| PRJNA312816 | ENA
Project description:Although multiple vital genes with strong effects on the tomato (Solanum lycopersicum) ripening process have been identified via the positional cloning of ripening mutants and cloning of ripening-related transcription factors (TFs), recent studies suggest that it is unlikely that we have fully characterized the gene regulatory networks underpinning this process. Here, combining comparative transcriptomics and expression QTLs, we identified 16 candidate genes involved in tomato fruit ripening and validated them through virus-induced gene silencing analysis. To further confirm the accuracy of the approach, one potential ripening regulator, SlWD40 (WD-40 repeats), was chosen for in-depth analysis. Co-expression network analysis indicated that master regulators such as RIN (ripening inhibitor) and NOR (nonripening) as well as vital TFs including FUL1 (FRUITFUL1), SlNAC4 (NAM, ATAF1,2, and CUC2 4), and AP2a (Activating enhancer binding Protein 2 alpha) strongly co-expressed with SlWD40. Furthermore, SlWD40 overexpression and RNAi lines exhibited substantially accelerated and delayed ripening phenotypes compared with the wild type, respectively. Moreover, transcriptome analysis of these transgenics revealed that expression patterns of ethylene biosynthesis genes, phytoene synthase, pectate lyase, and branched chain amino transferase 2, in SlWD40-RNAi lines were similar to those of rin and nor fruits, which further demonstrated that SlWD40 may act as an important ripening regulator in conjunction with RIN and NOR. These results are discussed in the context of current models of ripening and in terms of the use of comparative genomics and transcriptomics as an effective route for isolating causal genes underlying differences in genotypes.
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