BMP-4 suppresses progesterone production by inhibiting histone H3 acetylation of StAR in bovine granulosa cells in vitro.

This study examined the molecular mechanism by which BMP-4 inhibits progesterone production and the expression of genes involved in steroidogenesis. Granulosa cells were cultured in medium with or without BMP-4 for 0-96 h. BMP-4 inhibited progesterone secretion in granulosa cells and suppressed the expression of steroidogenic acute regulatory protein (StAR) at the mRNA and protein levels, whereas BMP-4 did not affect the proliferation of granulosa cells. In addition, we found that BMP-4 affected the expression of SR-B1 mRNA but not LDL-R in granulosa cells. To examine the protein-DNA interaction at specific sites within the StAR gene promoter, we used the quantitative real-time PCR and the ChIP technique. We demonstrated that BMP-4 suppresses the acetylation of histone H3 associated with the StAR promoter region at 48 and 72 h of culture in bovine granulosa cells. Our results showed for the first time that BMP-4 inhibited the acetylation of histone H3 associated with the StAR promoter region in bovine granulosa cells. Taken together, we propose that the inhibition of the acetylation of histone H3 associated with the StAR promoter region by BMP-4 may be one of the inhibitory molecular mechanisms of progesterone synthesis in granulosa cells. Our data suggested that theca cell-derived BMP-4 is important as a regulator of steroid hormone synthesis in granulosa cells during follicular development in the mammalian ovary.