Involvement of Histone Acetylation in Ovarian Steroid-induced Decidualization of Human Endometrial Stromal Cells

Nozomi Sakai,Tetsuo Maruyama,Rei Sakurai,Hirotaka Masuda,Yurie Yamamoto,Aki Shimizu,Ikuko Kishi,Hironori Asada,Satoshi Yamagoe,Yasunori Yoshimura

doi:10.1074/jbc.m211715200

Abstract

Histone acetyltransferases and histone deacetylases (HDACs) determine the acetylation status of histones, regulating gene transcription. Decidualization is the progestin-induced differentiation of estrogen-primed endometrial stromal cells (ESCs), which is crucial for implantation and maintenance of pregnancy. We here show that trichostatin A (TSA), a specific HDAC inhibitor, enhances the up-regulation of decidualization markers such as insulin-like growth factor binding protein-1 (IGFBP-1) and prolactin in a dose-dependent manner that is directed by 17beta-estradiol (E(2)) plus progesterone (P(4)) in cultured ESCs, but not glandular cells, both isolated from human endometrium. Morphological changes resembling decidual transformation were also augmented by co-addition of TSA. Acid urea triton gel analysis and immunoblot using acetylated histone type-specific antibodies demonstrated that treatment with E(2) plus P(4) significantly increased the levels of acetylated H3 and H4 whose increment was augmented by co-treatment with TSA. Chromatin immunoprecipitation assay revealed that treatment with E(2) plus P(4) increased the amount of proximal progesterone-responsive region of IGFBP-1 promoter associated with acetylated H4, which was dramatically enhanced by co-addition of TSA. Taken together, our results suggest that histone acetylation is deeply involved in differentiation of human ESCs and that TSA has a potential as an enhancer of decidualization through promotion of progesterone action.

Highlights

Histone acetyltransferases and histone deacetylases (HDACs) determine the acetylation status of histones, regulating gene transcription
We here show that trichostatin A (TSA), a specific HDAC inhibitor, enhances the up-regulation of decidualization markers such as insulin-like growth factor binding protein-1 (IGFBP-1) and prolactin in a dose-dependent manner that is directed by 17␤-estradiol (E2) plus progesterone (P4) in cultured endometrial stromal cells (ESCs), but not glandular cells, both isolated from human endometrium
Chromatin immunoprecipitation assay revealed that treatment with E2 plus P4 increased the amount of proximal progesterone-responsive region of IGFBP-1 promoter associated with acetylated H4, which was dramatically enhanced by co-addition of TSA

Summary

Histone Acetylation in Decidualization

Advances highlight the involvement of HATs in transcriptional activation and HDACs in transcriptional repression [17]. We have investigated the effect of TSA on ESCs in terms of ovarian steroid-induced differentiation induction to address how histone acetylation is involved in this process. We here show that TSA advances ovarian steroid-induced decidualization of ESCs isolated from human cycling endometrium. Histones H3 and H4 became acetylated upon decidualization, and the acetylated H4 was associated with the ovarian steroidinduced promoter activation of IGFBP-1, a typical decidualization marker gene, both of which were augmented by co-treatment with TSA.

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION