Dataset Information

Genome-wide analysis and functional prediction of the estrogen-regulated transcriptional response in the mouse uterus†.

ABSTRACT: The ovarian hormones estrogen and progesterone orchestrate the transcriptional programs required to direct functions of the uterus for initiation and maintenance of pregnancy. Estrogen, acting via estrogen receptor alpha, regulates gene expression by activating and repressing distinct genes involved in signaling pathways that regulate cellular and physiological responses including cell division, water influx, and immune cell recruitment. Historically, these transcriptional responses have been postulated to reflect a biphasic physiological response. In this study, we explored the transcriptional responses of the ovariectomized mouse uterus to 17?-estradiol (E2) by RNA-seq to obtain global expression profiles of protein-coding transcripts (mRNAs) and long noncoding RNAs (lncRNAs) following 0.5, 1, 2, and 6 hours of treatment. The E2-regulated mRNA and lncRNA expression profiles in the mouse uterus indicate an association between lncRNAs and mRNAs that regulate E2-driven pathways and reproductive phenotypes in the mouse. The transient E2-regulated transcriptome is reflected in the time-dependent shifting of biological processes regulated in the uterus in response to E2. Moreover, high expression of some conserved lncRNAs that are E2 regulated in the mouse uterus are predictive of low overall survival in endometrial carcinoma patients (e.g., H19, KCNQ1OT1, MIR17HG, and FTX). Collectively, this study (1) describes a genomic approach for identifying E2-regulated lncRNAs that may serve critical function in the uterus and (2) provides new insights into our understanding of the regulation of hormone-regulated transcriptional responses with implications in pregnancy and endometrial pathologies.

SUBMITTER: Vasquez YM

PROVIDER: S-EPMC7016285 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Genome-wide analysis and functional prediction of the estrogen-regulated transcriptional response in the mouse uterus†.

Vasquez Yasmin M YM Nandu Tulip S TS Kelleher Andrew M AM Ramos Enrique I EI Gadad Shrikanth S SS Kraus W Lee WL

Biology of reproduction 20200201 2

The ovarian hormones estrogen and progesterone orchestrate the transcriptional programs required to direct functions of the uterus for initiation and maintenance of pregnancy. Estrogen, acting via estrogen receptor alpha, regulates gene expression by activating and repressing distinct genes involved in signaling pathways that regulate cellular and physiological responses including cell division, water influx, and immune cell recruitment. Historically, these transcriptional responses have been po ...[more]

PMID: 31511857

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Project description:The growth and development of the uterus in response to 17β-estradiol (E2) is genetically controlled, with marked variation observed depending on the mouse strain studied. Previous work from our laboratory using inbred mice that are high (C57BL6/J; B6) or low (C3H/HeJ; C3H) responders to E2 has led to the identification of quantitative trait loci (QTL) associated with phenotypic variation in uterine growth and eosinophil infiltration. The mechanisms underlying differential responsiveness to E2, and the genes involved, are unknown. Therefore, we used a microarray approach to show association of distinct E2-regulated transcriptional signatures with genetically controlled high and low responses to E2. Among the 6,664 E2-responsive uterine transcripts, several reside within our previously identified QTL, including the ERα-tethering factor Runx1, demonstrated to enhance E2-mediated transcript regulation. The level of RUNX1 in uterine epithelial cells was shown to be 3.5-fold greater in B6 compared to C3H. Analysis of cellular functions in sets of strain-dependent E2-responsive transcripts indicated C3H-selective enrichment of apoptosis, consistent with a 7-fold increase in the apoptosis indicator CASP3, and a 2.4-fold decrease in the apoptosis inhibitor Naip1 in C3H vs. B6 following treatment with E2. Our novel insights into the mechanisms underlying the genetic control of tissue sensitivity to estrogen have great potential to advance understanding of individualized effects in physiological and disease states. Eight-week-old female B6, C3H, and (B6 × C3H)F1 (B6C3) hybrid mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Animals were ovariectomized at NIEHS, rested for 1 to 2 wk, and then subjected to treatment with either E2 (40.0 μg/kg BW injected i.p.) in 0.1 ml saline containing 0.25% ethanol, or ethanol/saline vehicle. Animals were euthanized and tissue collected at 2 or 24 h after injection. Uterine tissue from 3 animals per treatment group was collected, and snap-frozen in liquid nitrogen for subsequent RNA isolation. Frozen uterine tissue from three animals per treatment group was pulverized, then homogenized in Trizol (Invitrogen, Carlsbad, CA), and RNA was prepared according to the manufacturer's protocol. Isolated RNA was then further purified using the QIAGEN (Valencia, CA) RNeasy mini prep kit clean-up protocol. Gene expression analysis was conducted using Agilent Whole Mouse Genome 4x44 Multiplex format oligo arrays (014868; Agilent Technologies, Santa Clara, CA) following the Agilent 1-color microarray-based gene expression analysis protocol. Starting with 500 ng of total RNA, Cy3-labeled cRNA was produced according to the manufacturer's protocol. For each sample, 1.65 ug of Cy3-labeled cRNAs were fragmented and hybridized for 17 hours in a rotating hybridization oven. Slides were washed and then scanned with an Agilent Scanner.

Project description:Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the ER. The cellular response to ER stress involves complex transcriptional and translational changes, important to the survival of the cell. ER stress is a primary cause and a modifier of many human diseases. A first step to understanding how the ER stress response impacts human disease is to determine how the transcriptional response to ER stress varies among individuals. The genetic diversity of the eight mouse Collaborative Cross (CC) founder strains allowed us to determine how genetic variation impacts the ER stress transcriptional response. We used tunicamycin, a drug commonly used to induce ER stress, to elicit an ER stress response in mouse embryonic fibroblasts (MEFs) derived from the CC founder strains and measured their transcriptional responses. We identified hundreds of genes that differed in response to ER stress across these genetically diverse strains. Strikingly, inflammatory response genes differed most between strains; major canonical ER stress response genes showed relatively invariant responses across strains. To uncover the genetic architecture underlying these strain differences in ER stress response, we measured the transcriptional response to ER stress in MEFs derived from a subset of F1 crosses between the CC founder strains. We found a unique layer of regulatory variation that is only detectable under ER stress conditions. Over 80% of the regulatory variation under ER stress derives from cis-regulatory differences. This is the first study to characterize the genetic variation in ER stress transcriptional response in the laboratory mouse. Our findings indicate that the ER stress transcriptional response is highly variable among strains and arises from genetic variation in individual downstream response genes, rather than major signaling transcription factors. These results have important implications for understanding how genetic variation impacts the ER stress response, an important component of many human diseases.

Dataset Information

Genome-wide analysis and functional prediction of the estrogen-regulated transcriptional response in the mouse uterus†.

Publications

Genome-wide analysis and functional prediction of the estrogen-regulated transcriptional response in the mouse uterus†.

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