Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan.
Mol Cell Biochem. 2011 Feb;348(1-2):183-90. doi: 10.1007/s11010-010-0653-9. Epub 2010 Nov 12.
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.
这项研究探讨了 BMP-4 抑制孕激素产生和类固醇生成相关基因表达的分子机制。将颗粒细胞在含有或不含有 BMP-4 的培养基中培养 0-96 小时。BMP-4 抑制颗粒细胞中孕激素的分泌，并在 mRNA 和蛋白水平上抑制类固醇急性调节蛋白 (StAR) 的表达，而 BMP-4 并不影响颗粒细胞的增殖。此外，我们发现 BMP-4 影响颗粒细胞中 SR-B1 mRNA 的表达，但不影响 LDL-R。为了研究 StAR 基因启动子内特定部位的蛋白-DNA 相互作用，我们使用了定量实时 PCR 和 ChIP 技术。我们证明 BMP-4 在牛颗粒细胞培养的 48 和 72 小时抑制了与 StAR 启动子区域相关的组蛋白 H3 的乙酰化。我们的研究结果首次表明，BMP-4 抑制了与 StAR 启动子区域相关的组蛋白 H3 的乙酰化，在牛颗粒细胞中。总之，我们提出 BMP-4 抑制与 StAR 启动子区域相关的组蛋白 H3 的乙酰化可能是颗粒细胞中孕激素合成的抑制性分子机制之一。我们的数据表明，在哺乳动物卵巢的卵泡发育过程中，来自于卵泡膜细胞的 BMP-4 作为类固醇激素合成的调节剂非常重要。
