Single-cell Sequencing Reveals Transcriptional Dynamics Regulated by ERα in Mouse Ovaries

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2024 Nov 21

PMID 39570927

Authors

Qicai Hu

Yiqian Gui

Congcong Cao

Jun Xie

Huiru Tang

Affiliations

Soon will be listed here.

Abstract

Context: Estrogen receptor α (ERα) is a key regulator of reproductive function, particularly in ovarian development and function, yet the specifics of its role at the molecular level remain unclear.

Aims: The study aims to elucidate the molecular mechanisms of ERα-regulated transcriptional dynamics in ovarian cells using ERα knockout (αERKO) mice created via CRISPR/Cas9.

Methods: Single-cell RNA sequencing (scRNA-seq) was used to compare transcriptomes from individual ovarian cells in both wild type and αERKO mice. Bioinformatics analyses identified distinct cell populations and their transcriptional profiles post ERα deletion.

Key Results: Distinct oocyte and granulosa cell populations were identified, with ERα deletion disrupting the regulation of genes linked to ovarian infertility, the ovulation cycle, and steroidogenesis. Greb1 expression in granulosa cells was found to be ERα-dependent.

Conclusions: ERα deletion significantly alters the transcriptional landscape of ovarian cells, affecting genes and pathways central to ovarian function and the ovulation process.

Implications: The findings provide an in-depth, single-cell view of ERα's role in the reproductive system, offering insights that may lead to novel treatments for ovarian disorders.

Citing Articles

Acephate Exposure Induces Transgenerational Ovarian Developmental Toxicity by Altering the Expression of Follicular Growth Markers in Female Rats.

Alhazmi A, Nahdi S, Alwasel S, Harrath A Biology (Basel). 2025; 13(12.

PMID: 39765742 PMC: 11673910. DOI: 10.3390/biology13121075.

References

Gallardo T, John G, Shirley L, Contreras C, Akbay E, Haynie J . Genomewide discovery and classification of candidate ovarian fertility genes in the mouse. Genetics. 2007; 177(1):179-94. PMC: 2013718. DOI: 10.1534/genetics.107.074823. View

Deb S, Campbell B, Clewes J, Pincott-Allen C, Raine-Fenning N . Intracycle variation in number of antral follicles stratified by size and in endocrine markers of ovarian reserve in women with normal ovulatory menstrual cycles. Ultrasound Obstet Gynecol. 2012; 41(2):216-22. DOI: 10.1002/uog.11226. View

Laviolette L, Hodgkinson K, Minhas N, Perez-Iratxeta C, Vanderhyden B . 17β-estradiol upregulates GREB1 and accelerates ovarian tumor progression in vivo. Int J Cancer. 2014; 135(5):1072-84. PMC: 4235304. DOI: 10.1002/ijc.28741. View

Wang S, Zheng Y, Li J, Yu Y, Zhang W, Song M . Single-Cell Transcriptomic Atlas of Primate Ovarian Aging. Cell. 2020; 180(3):585-600.e19. DOI: 10.1016/j.cell.2020.01.009. View

Couse J, Hewitt S, Bunch D, Sar M, Walker V, Davis B . Postnatal sex reversal of the ovaries in mice lacking estrogen receptors alpha and beta. Science. 1999; 286(5448):2328-31. DOI: 10.1126/science.286.5448.2328. View

Piekorz R, Gingras S, Hoffmeyer A, Ihle J, Weinstein Y . Regulation of progesterone levels during pregnancy and parturition by signal transducer and activator of transcription 5 and 20alpha-hydroxysteroid dehydrogenase. Mol Endocrinol. 2004; 19(2):431-40. DOI: 10.1210/me.2004-0302. View

Tu X, Liu M, Tang J, Zhang Y, Shi Y, Yu L . The ovarian estrogen synthesis function was impaired in Y123F mouse and partly restored by exogenous FSH supplement. Reprod Biol Endocrinol. 2018; 16(1):44. PMC: 5934784. DOI: 10.1186/s12958-018-0365-7. View

Richards J . Maturation of ovarian follicles: actions and interactions of pituitary and ovarian hormones on follicular cell differentiation. Physiol Rev. 1980; 60(1):51-89. DOI: 10.1152/physrev.1980.60.1.51. View

Bourguet W, Germain P, Gronemeyer H . Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications. Trends Pharmacol Sci. 2000; 21(10):381-8. DOI: 10.1016/s0165-6147(00)01548-0. View

10.

Dietzel E, Weiskirchen S, Floehr J, Horiguchi M, Todorovic V, Rifkin D . Latent TGF-β binding protein-1 deficiency decreases female fertility. Biochem Biophys Res Commun. 2016; 482(4):1387-1392. DOI: 10.1016/j.bbrc.2016.12.046. View

11.

Hah N, Kraus W . Hormone-regulated transcriptomes: lessons learned from estrogen signaling pathways in breast cancer cells. Mol Cell Endocrinol. 2013; 382(1):652-664. PMC: 3844033. DOI: 10.1016/j.mce.2013.06.021. View

12.

Morris M, Meinsohn M, Chauvin M, Saatcioglu H, Kashiwagi A, Sicher N . A single-cell atlas of the cycling murine ovary. Elife. 2022; 11. PMC: 9545525. DOI: 10.7554/eLife.77239. View

13.

Payne A, Hales D . Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocr Rev. 2004; 25(6):947-70. DOI: 10.1210/er.2003-0030. View

14.

Zhang G, Sun X, Feng Y, Li B, Li Y, Yang F . Zearalenone exposure impairs ovarian primordial follicle formation via down-regulation of Lhx8 expression in vitro. Toxicol Appl Pharmacol. 2017; 317:33-40. DOI: 10.1016/j.taap.2017.01.004. View

15.

Fan H, Liu Z, Johnson P, Richards J . CCAAT/enhancer-binding proteins (C/EBP)-α and -β are essential for ovulation, luteinization, and the expression of key target genes. Mol Endocrinol. 2010; 25(2):253-68. PMC: 3386543. DOI: 10.1210/me.2010-0318. View

16.

Law N, Weck J, Kyriss B, Nilson J, Hunzicker-Dunn M . Lhcgr expression in granulosa cells: roles for PKA-phosphorylated β-catenin, TCF3, and FOXO1. Mol Endocrinol. 2013; 27(8):1295-310. PMC: 3725343. DOI: 10.1210/me.2013-1025. View

17.

Chantalat E, Valera M, Vaysse C, Noirrit E, Rusidze M, Weyl A . Estrogen Receptors and Endometriosis. Int J Mol Sci. 2020; 21(8). PMC: 7215544. DOI: 10.3390/ijms21082815. View

18.

Hewitt S, Winuthayanon W, Lierz S, Hamilton K, Donoghue L, Ramsey J . Role of ERα in Mediating Female Uterine Transcriptional Responses to IGF1. Endocrinology. 2017; 158(8):2427-2435. PMC: 5551553. DOI: 10.1210/en.2017-00349. View

19.

Mejia R, Waite C, Ascoli M . Activation of Gq/11 in the mouse corpus luteum is required for parturition. Mol Endocrinol. 2014; 29(2):238-46. PMC: 4318882. DOI: 10.1210/me.2014-1324. View

20.

Cluzet V, Devillers M, Petit F, Pierre A, Giton F, Airaud E . Estradiol promotes cell survival and induces Greb1 expression in granulosa cell tumors of the ovary through an ERα-dependent mechanism. J Pathol. 2021; 256(3):335-348. DOI: 10.1002/path.5843. View