Role of ER[alpha] in Mediating Female Uterine Transcriptional Responses to IGF1

Abstract Estrogen (E2) signaling through its nuclear receptor, E2 receptor α (ERα ) increases insulinlike growth factor 1 (IGF1) in the rodent uterus, which then initiates further signals via the IGF1 receptor. Directly administering IGF1 results in similar biological and transcriptional uterine res...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 2017-08, Vol.158 (8), p.2427
Main Authors: Hewitt, Sylvia C, Winuthayanon, Wipawee, Lierz, Sydney L, Hamilton, Katherine J, Donoghue, Lauren J, J Tyler Ramsey, Grimm, Sara A, Yukitomo Arao, Korach, Kenneth S
Format: Article
Language:English
Subjects:
Animal tissues
Binding sites
Biological effects
Chromatin
Endocrinology
Estrogen receptors
Estrogens
Immunoprecipitation
Insulin-like growth factor I
Livestock
Mice
Progesterone
Signaling
Transcription
Uterus
Wildlife
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Summary:Abstract Estrogen (E2) signaling through its nuclear receptor, E2 receptor α (ERα ) increases insulinlike growth factor 1 (IGF1) in the rodent uterus, which then initiates further signals via the IGF1 receptor. Directly administering IGF1 results in similar biological and transcriptional uterine responses. Our studies using global ERα -null mice demonstrated a loss of uterine biological responses of the uterus to E2 or IGF1 treatment, while maintaining transcriptional responses to IGF1. To address this discrepancy in the need for uterine ERα in mediating the IGF1 transcriptional vs growth responses, we assessed the IGF1 transcriptional responses in Pgr Cre + Esr1 f/f (called ERα UtcKO) mice, which selectively lack ERα in progesterone receptor (PGR) expressing cells, including all uterine cells, while maintaining ERα expression in other tissues and cells that do not express Pgr . Additionally, we profiled IGF1-induced ERα binding sites in uterine chromatin using chromatin immunoprecipitation sequencing. Herein, we explore the transcriptional and molecular signaling that underlies our findings to refine our understanding of uterine IGF1 signaling and identify ERα -mediated and ERα -independent uterine transcriptional responses. Defining these mechanisms in vivo in whole tissue and animal contexts provides details of nuclear receptor mediated mechanisms that impact biological systems and have potential applicability to reproductive processes of humans, livestock and wildlife. After treatment with IGF1, we compared transcriptional profiles of wild-type and ERα null tissues to ERα ChIP-seq data to find ER-α -independent and ER-α -dependent uterine responses to IGF1.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2017-00349