Publication Date

11-25-2021

Journal

Communications Biology

DOI

10.1038/s42003-021-02849-w

PMID

34824385

PMCID

PMC8617273

PubMedCentral® Posted Date

11-25-2021

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Animals, Cell Differentiation, Cell Proliferation, DNA Demethylation, Female, Granulosa Cells, Mice, Ovarian Follicle, Reproductive biology, DNA methylation

Abstract

During ovarian follicular development, granulosa cells proliferate and progressively differentiate to support oocyte maturation and ovulation. To determine the underlying links between proliferation and differentiation in granulosa cells, we determined changes in 1) the expression of genes regulating DNA methylation and 2) DNA methylation patterns, histone acetylation levels and genomic DNA structure. In response to equine chorionic gonadotropin (eCG), granulosa cell proliferation increased, DNA methyltransferase (DNMT1) significantly decreased and Tet methylcytosine dioxygenase 2 (TET2) significantly increased in S-phase granulosa cells. Comprehensive MeDIP-seq analyses documented that eCG treatment decreased methylation of promoter regions in approximately 40% of the genes in granulosa cells. The expression of specific demethylated genes was significantly increased in association with specific histone modifications and changes in DNA structure. These epigenetic processes were suppressed by a cell cycle inhibitor. Based on these results, we propose that the timing of sequential epigenetic events is essential for progressive, stepwise changes in granulosa cell differentiation.

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