Large-scale DNA demethylation occurs in proliferating ovarian granulosa cells during mouse follicular development

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. Tomoko Kawai et al. investigate DNA methylation patterns during granulosa cell differentiation and proliferation. Their results suggest that sequential epigenetic events are essential for progressive changes in granulosa cell differentiation.

Automated summary

Research has shown that through modulating processes such as DNA methylation levels and histone modifications, equine chorionic gonadotropin can promote the proliferation and differentiation of granulosa cells, and the timing and sequence of these epigenetic events are crucial for the progression of granulosa cell differentiation.