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 (ERα), 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 17β-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.

ORGANISM(S): Mus musculus

PROVIDER: GSE133158 | GEO | 2019/09/16

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:The uterus, a female reproductive organ regulated by the sex hormones estrogen and progesterone, undergoes periodic cyclical changes. The estrous cycle refers to the reproductive cycle in non-primate mammalian females. During the mouse estrous cycle, the uterus undergoes various physiological changes as a result of dynamic hormonal changes. Accurate regulation of these changes is crucial for the establishment of a successful pregnancy. Notably, estrogen plays an important role in the regulation of the proestrus and estrus stages of the estrous cycle. Family with sequence similarity 3 (Fam3) is a cytokine-like gene family with four members: Fam3a, Fam3b, Fam3c, and Fam3d. Expression and regulation of the Fam3 family members in mouse uterine physiology remain largely unknown. Therefore, this study aimed to investigate the expression of Fam family members in the uterus during the estrous cycle and evaluate its regulation by estrogen using a mouse model. Analysis of mouse uterine RNA sequencing data revealed upregulated expression of Fam3b, Fam3c, and Fam3d during the proestrus and estrus stages. Fam3d expression was dynamically regulated during the estrous cycle, with high expression levels during the proestrus and estrus stages. To investigate whether Fam3d expression is regulated by estrogen, we administered estradiol (E2) to ovariectomized mice at different time points. Fam3d expression was highest 24 h after E2 injection, suggesting that estrogen plays a crucial role in regulating Fam3d expression. Furthermore, inhibition experiments using the estrogen receptor alpha (ERα) antagonist ICI revealed that estrogen regulates Fam3d expression through the ERα-mediated pathway. Immunofluorescence staining demonstrated that FAM3D was exclusively expressed in the luminal and glandular epithelia but not in the stroma. Additionally, FAM3D was predominantly localized in the cytoplasm, particularly in the apical region, and not in the nucleus. These findings provide valuable insights into the potential role of Fam3d in the uterus and lay the groundwork for future research on its function and significance in uterine physiology.

Project description:The cellular responses to the steroid hormones, estrogen (E2), and progesterone (P4) are governed by their cognate receptor’s transcriptional output. Although multiple mechanisms including the tissue-specific coactivators dictate these transcriptional signatures, the feed-forward mechanisms, that evolved to coordinate the cell-type specific transcriptional fulcrums for steroid receptors are not yet identified. In this report, we found that a common feed-forward mechanism between GREB1 and steroid receptors governs the differential effect of GREB1 on steroid hormones in a physiological or pathological context. We found that in physiological (receptive) endometrium, GREB1 is essential for progesterone but not estrogenic responses, whereas in endometriosis, an E2-dependent endometrial pathology, it pre-dominantly mediates estrogenic actions. Specifically, the deletion of GREB1 curtails endometrial receptivity and decidualization, owing to impaired P4-dependent stromal cell proliferation. In contrast, GREB1 is not required for E2-mediated epithelial proliferation of the receptive uterus. Of mechanism, in receptive endometrium, progesterone-induced GREB1 physically interacts with the progesterone receptor on chromatin and functions as a cofactor in a positive feedback mechanism to selectively regulate P4-responses. In pathological conditions (endometriosis), ablation of GREB1 led to the development of smaller endometriotic lesions in mice and reduced E2-driven proliferation of human endometriotic cells. Moreover, E2-induced GREB1 modulated the E2-dependent target gene expression in a feed-forward mechanism. Collectively, acting as a downstream effector, GREB1 governs either P4-responses or E2-responses depending on the physiological or pathological setting. Importantly, this differential action of GREB1 is exerted by a common feed-forward mechanism between GREB1 and steroid receptors, which conceptually advances our understanding of the mechanism(s) that underlie the distinct cell- and tissue-specific actions of steroid hormones.

Dataset Information

Genome-wide Analysis and Functional Prediction of the Estrogen-Regulated Transcriptional Response in the Mouse Uterus

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets