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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.
Highlights
During ovarian follicular development, granulosa cells proliferate and progressively differentiate to support oocyte maturation and ovulation
In granulosa cells of preovulatory follicles (PFs) isolated from mouse ovaries 48 h after equine chorionic gonadotropin (eCG) injection, the expression levels of Dnmt[1] were significantly decreased compared with those in antral follicles isolated from mice before eCG injection (Fig. 1a; 0 h)
Transcription factors play a key role in gene activation, gene expression patterns in each cell depend on changes in cell-specific chromatin structure, notably the open chromatin structure in the S-phase of the cell cycle and in promoter and enhancer regions of activated genes[31,32,33]
Summary
Granulosa cells proliferate and progressively differentiate to support oocyte maturation and ovulation. 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. Methylation events are reversed and regulated by TET enzymes (Tet methylcytosine dioxygenases) that convert DNA methylcytosine to 5-hydroxymethylcytosine[7,8] These pathways control or modify the methylated CpG islands found frequently in promoters of key regulatory genes to induce specific gene expression patterns. Mutant mice lacking the Ccnd[2] gene that encodes cyclin D2 exhibit female infertile phenotypes characterized by small follicles, depletion of granulosa cells, and altered gene expression patterns, including the lack of Lhcgr[18], suggesting that cell proliferation might be involved in the differentiation of granulosa cells and the large-scale epigenetic changes that occur during follicular development and ovulation. The studies described were undertaken to analyze granulosa cells as a model to determine the underlying mechanisms by which DNA methylation changes dramatically in highly proliferative cells
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