Molecular mechanism of FSHR expression induced by BMP15 in human granulosa cells
Molecular mechanism of FSHR expression induced by BMP15 in human granulosa cells
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DOI：
10.1007/s10815-019-01469-y
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发表时间：
2019-06-01
影响因子：
3.1
通讯作者：
Kikkawa, Fumitaka
中科院分区：
文献类型：
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作者：
Shimizu, Ken;Nakamura, Tomoko;Kikkawa, Fumitaka
目的卵泡刺激素受体（FSHR）在颗粒细胞中的表达是促进卵泡生长的关键。虽然FSHR的表达已被报道是表观遗传调控，但其机制尚不清楚。卵母细胞和颗粒细胞之间的合作对于卵泡的正常生长也是必不可少的。在卵母细胞衍生因子中，骨形态发生蛋白15（BMP 15）促进卵泡生长，并被认为具有表观遗传效应。我们研究了BMP 15在人类颗粒细胞中获得FSHR的作用。MethodsImmortalized非黄体化的人类颗粒细胞（HGrC 1）细胞刺激，用阿司他丁A（TSA）或BMP 15来分析FSHR表达，组蛋白修饰，和USF 1/2结合在FSHR启动子区。在有或没有BMP 15、SB 203580和LDN 193189的情况下检查组蛋白乙酰转移酶（HAT）活性和Smad 1/5/8和p38 MAPK的磷酸化。CYP 19 A1的表达和雌二醇的生产也studied.ResultsTSA和BMP 15诱导FSHR mRNA的表达在一个剂量依赖性的方式和组蛋白的修改与USF 1/2的结合增加观察。BMP 15增加FSHR蛋白表达，而LDN 193189抑制FSHR蛋白表达。BMP 15增加Smad 1/5/8的磷酸化，并显著增加HAT活性，这被LDN 193189抑制，但不被SB 203580抑制。BMP 15增加p38 MAPK和USF 1的磷酸化。LDN 193189抑制BMP 15诱导的p38 MAPK和USF 1磷酸化，而SB 203580抑制USF 1磷酸化。结论BMP 15通过Smad和非Smad途径诱导人卵巢颗粒细胞FSHR表达。BMP 15诱导FSHR的这种机制可用于控制卵泡生长。
PurposeFollicle-stimulating hormone receptor (FSHR) expression in granulosa cells is critical in enabling follicles to achieve accelerated growth. Although FSHR expression has been reported to be epigenetically regulated, the mechanism is unclear. Cooperation between oocytes and granulosa cells is also essential for normal follicular growth. Among oocyte-derived factors, bone morphogenetic protein 15 (BMP15) promotes follicular growth and is suggested to have epigenetic effects. We examined the role of BMP15 in the acquirement of FSHR in human granulosa cells.MethodsImmortalized non-luteinized human granulosa (HGrC1) cells were stimulated with trichostatin A (TSA) or BMP15 to analyze FSHR expression, histone modifications, and USF1/2 binding at the FSHR promoter region. Histone acetyl transferase (HAT) activity and phosphorylation of Smad 1/5/8 and p38 MAPK were examined with or without BMP15, SB203580, and LDN193189. CYP19A1 expression and estradiol production were also studied.ResultsTSA and BMP15 induced FSHR mRNA expression in a dose-dependent manner and histone modifications were observed with increased binding of USF1/2. BMP15 increased FSHR protein expression, which was suppressed by LDN193189. BMP15 increased phosphorylation of Smad 1/5/8 and significantly increased HAT activity, which was inhibited by LDN193189, but not by SB203580. BMP15 increased phosphorylation of p38 MAPK and USF1. LDN193189 suppressed BMP15-induced phosphorylation of both p38 MAPK and USF1, whereas SB203580 suppressed the phosphorylation of USF1. BMP15 increased CYP19A1 mRNA expression and estradiol production.ConclusionBMP15 induced FSHR expression in human granulosa cells through Smad and non-Smad pathways. This mechanism of FSHR induction by BMP15 may be utilized for controlling follicular growth.