Histone deacetylase inhibition and progesterone act synergistically to stimulate baboon glycodelin gene expression

Abstract

During the late luteal phase of the menstrual cycle and early pregnancy, the major secretory product of the uterine glandular epithelial cells in humans and non-human primates is glycodelin. Previous studies using Ishikawa cells, a human endometrial cell line, have shown that a chimeric plasmid containing the baboon glycodelin promoter responds to progestins but the response is modest compared with the induction of glycodelin seen in vivo and in gene array analysis. A recent report indicating that the histone deacetylase inhibitor trichostatin A (TSA) promoted glycodelin expression prompted us to examine its mechanism of action. In Ishikawa cells transfected with the baboon glycodelin promoter, TSA and the synthetic progestin medroxyprogesterone acetate both stimulated expression of the reporter and the combined treatment produced a synergistic effect. The effect of TSA and progestin was absent when the same promoter constructs were transfected into COS-1 cells, a kidney cell line, and a TSA effect but no progestin effect was observed in T47D cells, a mammary cell line. Through deletion analysis, the TSA action was localized to the K67/K52 region of the baboon glycodelin promoter, a region which contains the proximal Sp1 site. Deletions of this same region had no effect on progestin responsiveness. Our findings indicate that at least two regions of the glycodelin promoter are important for the normal induction of glycodelin expression. Non-target cells may lack factors which act on the response elements resulting in the restriction of expression to the appropriate target tissue.

Trichostatin A Stimulates Steroid 5α-Reductase Gene Expression in Rat C6 Glioma Cells via a Mechanism Involving Sp1 and Sp3 Transcription Factors

“…Furthermore, sodium butyrate has been shown to induce the activation of epithelial sodium channel gene expression in human colorectal tumor cells (Zeissig et al 2007). Moreover, TSA has also been shown to activate cyclooxygenese-1 gene transcription in human astrocytes (Taniura et al 2002) and baboon glycodelin gene transcription in COS cells (Jaffe et al 2007). In contrast, TSA has been reported to induce the inhibition of TGF-b-induced collagen expression in skin fibroblasts (Ghosh et al 2007).…”

“…On the other hand, the biological significance of histone acetylation and deacetylation in the regulation of gene transcription has been investigated, and considerable evidence for suggesting a potential role of histone acetylation has recently been accumulated. In particular, the effects of HDAC inhibitors on the promoter activities of various genes have been actively examined, and these inhibitors have been suggested to modulate the gene transcription through the transcription factor Sp1 and Sp3 (Choi et al 2002;Ghosh et al 2007;Jaffe et al 2007;Taniura et al 2002;Walker et al 2001;Zeissig et al 2007). Together with our previous findings (Morita et al 2004(Morita et al , 2005(Morita et al , 2006(Morita et al , 2009Morita and Her 2008), these observations enable us to hypothesize that HDAC inhibitors may induce the differentiation of glial cells probably through the production of 5α-reduced steroid metabolites, resulting in the enhancement of BDNF production, which may somewhat contribute to their antidepressant-like actions.…”

Inflammation in Reproductive Disorders

“…28 The gene encoding GdA is regulated by a promoter that contains 4 canonical P responsive elements, 21 however its transcriptional regulation is complex. 29 Glycodelin-A transcription and translation can be stimulated by progestins 30 and possibly relaxin 31 in vitro and by human chorionic gonadtropin infusion into the baboon uterus in vivo. 32 We postulate that hormones secreted in early pregnancy from the corpus luteum and growing trophoblast stimulate the local production of GdA from endometrial glands.…”

Natural and recombinant human glycodelin activate a proapoptotic gene cascade in monocyte cells

“…The postulated regulators of cyclical GdA secretion in the endometrium include progesterone, relaxin, and human chorionic gonadotropin (hCG) [8,9]. Ligand-activated progesterone receptors A and B can activate GdA gene transcription [10], but it appears that consensus progesterone response elements (PREs) in the proximal gene promoter are synergized by other transcription factors [4,11,12].…”