title: Critical role of histone acetylation by p300 in human placental 11β-HSD2 expression.
abstract: BACKGROUND
  Fetal overexposure to glucocorticoids leads to growth restriction. Optimal fetal glucocorticoid level is ensured by the expression of cortisol-inactivating enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in placental syncytiotrophoblasts. The transcription factor selective promoter factor 1 (Sp1) is known to up-regulate 11β-HSD2 expression in the presence of enhanced histone acetylation in syncytiotrophoblasts, but the mechanisms underlying histone acetylation remain unknown.
  
  
  OBJECTIVE
  The role of p300 in histone acetylation associated with 11β-HSD2 expression in syncytiotrophoblasts was investigated.
  
  
  METHODS
  Distribution of p300 in human placenta was studied with immunohistochemistry. The role of p300 in histone-3 (H3) acetylation in association with 11β-HSD2 expression was investigated in cultured primary human placental trophoblasts in the presence of small interfering RNA (siRNA)-mediated knockdown of p300, p300 inhibitor C646, or p300 overexpression. The interaction of Sp1 and p300 was studied with chromatin immunoprecipitation and coimmunoprecipitation.
  
  
  RESULTS
  Intense staining of p300 was found in the nuclei of trophoblasts. Levels of p300 and acetyl H3K9 and H3K27 associated with 11β-HSD2 promoter were increased in the course of syncytialization and by cAMP pathway activation. Chromatin immunoprecipitation and coimmunoprecipitation revealed p300 and Sp1 on 11β-HSD2 promoter and in the same protein complex in the syncytiotrophoblasts. Overexpression of p300 enhanced 11β-HSD2 expression, which was attenuated by Sp1 knockdown, whereas p300 knockdown and C646 reduced both basal and cAMP-stimulated acetylation of H3K9 and H3K27 associated with 11β-HSD2 expression.
  
  
  CONCLUSIONS
  Interaction of p300 with Sp1 plays a crucial role in histone acetylation associated with 11β-HSD2 expression in syncytiotrophoblasts, which may have important implications in the establishment of the placental glucocorticoid barrier in gestation.
authors.affiliation: School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Jianneng
authors.initials: J
authors.lastname: Li
authors.forename: Wangsheng
authors.initials: W
authors.lastname: Wang
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.forename: Weihua
authors.initials: W
authors.lastname: Wang
authors.forename: Wenjiao
authors.initials: W
authors.lastname: Li
authors.forename: Qun
authors.initials: Q
authors.lastname: Shu
authors.forename: Zi-Jiang
authors.initials: ZJ
authors.lastname: Chen
authors.forename: Kang
authors.initials: K
authors.lastname: Sun
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics / Q000378:metabolism*; D000107:Acetylation / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006657:Histones / Q000378:metabolism*; D006801:Humans; D010920:Placenta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010929:Placentation / Q000187:drug effects; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport; D034622:RNA Interference; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000242:Cyclic AMP; D004791:Enzyme Inhibitors; D006657:Histones; D011994:Recombinant Proteins; D016329:Sp1 Transcription Factor; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C468387:HSD11B2 protein, human