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Estrogen receptor ? drives pro-resilient transcription in mouse models of depression.

ABSTRACT: Most people exposed to stress do not develop depression. Animal models have shown that stress resilience is an active state that requires broad transcriptional adaptations, but how this homeostatic process is regulated remains poorly understood. In this study, we analyze upstream regulators of genes differentially expressed after chronic social defeat stress. We identify estrogen receptor ? (ER?) as the top regulator of pro-resilient transcriptional changes in the nucleus accumbens (NAc), a key brain reward region implicated in depression. In accordance with these findings, nuclear ER? protein levels are altered by stress in male and female mice. Further, overexpression of ER? in the NAc promotes stress resilience in both sexes. Subsequent RNA-sequencing reveals that ER? overexpression in NAc reproduces the transcriptional signature of resilience in male, but not female, mice. These results indicate that NAc ER? is an important regulator of pro-resilient transcriptional changes, but with sex-specific downstream targets.

SUBMITTER: Lorsch ZS

PROVIDER: S-EPMC5856766 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Estrogen receptor α drives pro-resilient transcription in mouse models of depression.

Lorsch Zachary S ZS Loh Yong-Hwee Eddie YE Purushothaman Immanuel I Walker Deena M DM Parise Eric M EM Salery Marine M Cahill Michael E ME Hodes Georgia E GE Pfau Madeline L ML Kronman Hope H Hamilton Peter J PJ Issler Orna O Labonté Benoit B Symonds Ann E AE Zucker Matthew M Zhang Tie Yuan TY Meaney Michael J MJ Russo Scott J SJ Shen Li L Bagot Rosemary C RC Nestler Eric J EJ

Nature communications 20180316 1

Most people exposed to stress do not develop depression. Animal models have shown that stress resilience is an active state that requires broad transcriptional adaptations, but how this homeostatic process is regulated remains poorly understood. In this study, we analyze upstream regulators of genes differentially expressed after chronic social defeat stress. We identify estrogen receptor α (ERα) as the top regulator of pro-resilient transcriptional changes in the nucleus accumbens (NAc), a key ...[more]

PMID: 29549264

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Project description:Estrogen receptor-α (ESR1) is an important transcriptional regulator in the mammalian oviduct, however ESR1-dependent regulation of the transcriptome of this organ is not well defined, especially at the genomic level. The objective of this study was therefore to investigate estradiol- and ESR1-dependent regulation of the transcriptome of the oviduct using transgenic mice, both with (ESR1KO) and without (wild-type, WT) a global deletion of ESR1. Oviducts were collected from ESR1KO and WT littermates at 23 days of age, or ESR1KO and WT mice were treated with 5 IU PMSG to stimulate follicular development and the production of ovarian estradiol, and the oviducts collected 48 h later. RNA extracted from whole oviducts was hybridized to Affymetrix Genechip Mouse Genome 430-2.0 arrays (n = 3 arrays per genotype and treatment) or reverse transcribed to cDNA for analysis of the expression of selected mRNAs by real-time PCR. Following microarray analysis, a statistical two-way ANOVA and pairwise comparison (LSD test) revealed 2428 differentially expressed transcripts (DEG's, P < 0.01). Genotype affected the expression of 2215 genes, treatment (PMSG) affected the expression of 465 genes, and genotype x treatment affected the expression of 438 genes. With the goal of determining estradiol/ESR1-regulated function, gene ontology (GO) and bioinformatic pathway analyses were performed on DEG's in the oviducts of PMSG-treated ESR1KO versus PMSG-treated WT mice. Significantly enriched GO molecular function categories included binding and catalytic activity. Significantly enriched GO cellular component categories indicated the extracellular region. Significantly enriched GO biological process categories involved a single organism, modulation of a measurable attribute and developmental processes. Bioinformatic analysis revealed ESR1-regulation of the immune response within the oviduct as the primary canonical pathway. In summary, a transcriptomal profile of estradiol- and ESR1-regulated gene expression and related bioinformatic analysis is presented to increase our understanding of how estradiol/ESR1 affects function of the oviduct, and to identify genes that may be proven as important regulators of fertility in the future.

Dataset Information

Estrogen receptor ? drives pro-resilient transcription in mouse models of depression.

Publications

Estrogen receptor α drives pro-resilient transcription in mouse models of depression.

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