ERβ in Granulosa Cell Tumors and Its Clinical Potential

Birgersson, Madeleine; Indukuri, Rajitha; Antonson, Per; Nalvarte, Ivan; Archer, Amena; Williams, Cecilia

doi:10.1210/endocr/bqad063

Cited by 6 publications

(1 citation statement)

References 115 publications

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“…Previous microarray and RNA-sequencing (RNA-seq) comparisons of granulosa cells from WT and ERβKO rodents, identified differences in FSH and LH target gene expression (e.g., Lhcgr , Cyp11a1 , Cyp19a1 , Runx2 , and Ptgs2 ), confirming the significance of ERβ during folliculogenesis and ovulation [ 29 , 30 ]. However, the exact mechanism of ERβ in the ovary, including its genome-wide endogenous chromatin binding, cross talk, and direct transcriptional impact has not been determined [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

Ovarian ERβ cistrome and transcriptome reveal chromatin interaction with LRH-1

Birgersson,

Indukuri,

Lindquist

et al. 2023

BMC Biol

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Background Estrogen receptor beta (ERβ, Esr2) plays a pivotal role in folliculogenesis and ovulation, yet its exact mechanism of action is mainly uncharacterized. Results We here performed ERβ ChIP-sequencing of mouse ovaries followed by complementary RNA-sequencing of wild-type and ERβ knockout ovaries. By integrating the ERβ cistrome and transcriptome, we identified its direct target genes and enriched biological functions in the ovary. This demonstrated its strong impact on genes regulating organism development, cell migration, lipid metabolism, response to hypoxia, and response to estrogen. Cell-type deconvolution analysis of the bulk RNA-seq data revealed a decrease in luteal cells and an increased proportion of theca cells and a specific type of cumulus cells upon ERβ loss. Moreover, we identified a significant overlap with the gene regulatory network of liver receptor homolog 1 (LRH-1, Nr5a2) and showed that ERβ and LRH-1 extensively bound to the same chromatin locations in granulosa cells. Using ChIP-reChIP, we corroborated simultaneous ERβ and LRH-1 co-binding at the ERβ-repressed gene Greb1 but not at the ERβ-upregulated genes Cyp11a1 and Fkbp5. Transactivation assay experimentation further showed that ERβ and LRH-1 can inhibit their respective transcriptional activity at classical response elements. Conclusions By characterizing the genome-wide endogenous ERβ chromatin binding, gene regulations, and extensive crosstalk between ERβ and LRH-1, along with experimental corroborations, our data offer genome-wide mechanistic underpinnings of ovarian physiology and fertility.

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Section: Introductionmentioning

confidence: 99%