The Sp1 transcription factor is crucial for the expression of 11β-hydroxysteroid dehydrogenase type 2 in human placental trophoblasts

J. N. Li, Y. C. Ge, Z. Yang, C. M. Guo, T. Duan, Leslie Myatt, H. Guan, K. Yang, Kang Sun

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Context: Overexposure of the fetus to glucocorticoids early in gestation is detrimental to fetal development. Glucocorticoid concentrations in the fetal circulation are kept low by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2, encoded by HSD11B2) in the placental syncytiotrophoblasts. However, cytotrophoblasts, the progenitors of syncytiotrophoblasts, express low levels of 11β-HSD2. Here we studied the molecular mechanisms underlying 11β-HSD2 induction upon syncytialization. Methods: Freshly isolated human term placental cytotrophoblasts and in vitro differentiated syncytiotrophoblasts were examined to determine the methylation status of HSD11B2 promoter. The transcription factor responsible for 11β-HSD2 induction was identified by observing its expression upon syncytialization, the effect of its attenuation, and its binding to the HSD11B2 promoter. Results: 11β-HSD2 expression was markedly increased upon syncytialization in vitro. No methylation differences of HSD11B2 promoter were found between cytotrophoblasts and syncytiotrophoblasts. Expression of the transcription factor Sp1 was markedly induced during syncytialization and further increased by activation of the cAMP pathway, which correlated with 11β-HSD2 expression. Importantly, small interfering RNA-mediated knockdown of Sp1 expression or inhibition of Sp1 activity with mithramycin A markedly attenuated not only basal but also cAMP pathway-stimulated expression of 11β-HSD2 in the syncytiotrophoblasts. Stimulation of the cAMP pathway also increased the binding of Sp1 and RNA polymerase II to HSD11B promoter in syncytiotrophoblasts. Concomitantly, acetylation at histone H3K9 was increased whereas methylation at histone H3K9 was decreased. Conclusions: 11β-HSD2 induction upon syncytialization is at least in part due to the increased expression of Sp1 upon activation of the cAMP pathway rather than the differential methylation of the HSD11B2 promoter.

Original languageEnglish (US)
JournalJournal of Clinical Endocrinology and Metabolism
Volume96
Issue number6
DOIs
StatePublished - Jun 2011
Externally publishedYes

Fingerprint

11-beta-Hydroxysteroid Dehydrogenases
Sp1 Transcription Factor
Methylation
Trophoblasts
Histones
Glucocorticoids
Chemical activation
Acetylation
RNA Polymerase II
Small Interfering RNA
Transcription Factors
Fetal Development
Fetus

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

The Sp1 transcription factor is crucial for the expression of 11β-hydroxysteroid dehydrogenase type 2 in human placental trophoblasts. / Li, J. N.; Ge, Y. C.; Yang, Z.; Guo, C. M.; Duan, T.; Myatt, Leslie; Guan, H.; Yang, K.; Sun, Kang.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 96, No. 6, 06.2011.

Research output: Contribution to journalArticle

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abstract = "Context: Overexposure of the fetus to glucocorticoids early in gestation is detrimental to fetal development. Glucocorticoid concentrations in the fetal circulation are kept low by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2, encoded by HSD11B2) in the placental syncytiotrophoblasts. However, cytotrophoblasts, the progenitors of syncytiotrophoblasts, express low levels of 11β-HSD2. Here we studied the molecular mechanisms underlying 11β-HSD2 induction upon syncytialization. Methods: Freshly isolated human term placental cytotrophoblasts and in vitro differentiated syncytiotrophoblasts were examined to determine the methylation status of HSD11B2 promoter. The transcription factor responsible for 11β-HSD2 induction was identified by observing its expression upon syncytialization, the effect of its attenuation, and its binding to the HSD11B2 promoter. Results: 11β-HSD2 expression was markedly increased upon syncytialization in vitro. No methylation differences of HSD11B2 promoter were found between cytotrophoblasts and syncytiotrophoblasts. Expression of the transcription factor Sp1 was markedly induced during syncytialization and further increased by activation of the cAMP pathway, which correlated with 11β-HSD2 expression. Importantly, small interfering RNA-mediated knockdown of Sp1 expression or inhibition of Sp1 activity with mithramycin A markedly attenuated not only basal but also cAMP pathway-stimulated expression of 11β-HSD2 in the syncytiotrophoblasts. Stimulation of the cAMP pathway also increased the binding of Sp1 and RNA polymerase II to HSD11B promoter in syncytiotrophoblasts. Concomitantly, acetylation at histone H3K9 was increased whereas methylation at histone H3K9 was decreased. Conclusions: 11β-HSD2 induction upon syncytialization is at least in part due to the increased expression of Sp1 upon activation of the cAMP pathway rather than the differential methylation of the HSD11B2 promoter.",
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AU - Li, J. N.

AU - Ge, Y. C.

AU - Yang, Z.

AU - Guo, C. M.

AU - Duan, T.

AU - Myatt, Leslie

AU - Guan, H.

AU - Yang, K.

AU - Sun, Kang

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N2 - Context: Overexposure of the fetus to glucocorticoids early in gestation is detrimental to fetal development. Glucocorticoid concentrations in the fetal circulation are kept low by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2, encoded by HSD11B2) in the placental syncytiotrophoblasts. However, cytotrophoblasts, the progenitors of syncytiotrophoblasts, express low levels of 11β-HSD2. Here we studied the molecular mechanisms underlying 11β-HSD2 induction upon syncytialization. Methods: Freshly isolated human term placental cytotrophoblasts and in vitro differentiated syncytiotrophoblasts were examined to determine the methylation status of HSD11B2 promoter. The transcription factor responsible for 11β-HSD2 induction was identified by observing its expression upon syncytialization, the effect of its attenuation, and its binding to the HSD11B2 promoter. Results: 11β-HSD2 expression was markedly increased upon syncytialization in vitro. No methylation differences of HSD11B2 promoter were found between cytotrophoblasts and syncytiotrophoblasts. Expression of the transcription factor Sp1 was markedly induced during syncytialization and further increased by activation of the cAMP pathway, which correlated with 11β-HSD2 expression. Importantly, small interfering RNA-mediated knockdown of Sp1 expression or inhibition of Sp1 activity with mithramycin A markedly attenuated not only basal but also cAMP pathway-stimulated expression of 11β-HSD2 in the syncytiotrophoblasts. Stimulation of the cAMP pathway also increased the binding of Sp1 and RNA polymerase II to HSD11B promoter in syncytiotrophoblasts. Concomitantly, acetylation at histone H3K9 was increased whereas methylation at histone H3K9 was decreased. Conclusions: 11β-HSD2 induction upon syncytialization is at least in part due to the increased expression of Sp1 upon activation of the cAMP pathway rather than the differential methylation of the HSD11B2 promoter.

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