title: Increased Krüppel-like factor 12 in recurrent implantation failure impairs endometrial decidualization by repressing Nur77 expression.
abstract: BACKGROUND
  Decidualization is a prerequisite for successful implantation and the establishment of pregnancy. A critical role of impaired decidualization in subfertility has been established. In human endometrial stromal cells (hESCs), Krüppel-like factor 12 (KLF12) and Nur77 are novel regulators of decidualization. We investigated whether KLF12 impaired the decidualization of hESCs in recurrent implantation failure (RIF) patients.
  
  
  METHODS
  Endometrial tissues and hESCs were collected from RIF patients (n = 34) and fertile controls (n = 30) for in vitro analysis. Primary hESCs isolated from RIF endometrial tissues were used to evaluate the biological functions of KLF12 and Nur77. In addition, their molecular mechanisms were investigated by adenovirus-mediated overexpression. Gene expression regulation was examined by real-time-quantitative PCR (qRT-PCR), immunostaining and luciferase reporter assay. Further, blastocyst-like spheroid (BLS) and blastocyst implantation models were performed to examine the roles of KLF12 and Nur77 during embryo expansion on hESCs.
  
  
  RESULTS
  hESCs from the RIF patients showed a poor decidual response, mainly characterized by decreased decidual prolactin (dPRL) secretion, impaired transformation and limited BLS expansion. In addition, KLF12 expression was increased in endometrial tissues from the RIF patients compared with those from the fertile controls, especially in stromal compartments. The opposite results were observed for Nur77 expression in these tissues. KLF12 repressed hESC decidualization by decreasing Nur77 expression. Mechanistically, KLF12 bound to a conserved site in the Nur77 promoter region. Nur77 overexpression significantly reversed the KLF12-mediated repression of dPRL expression, decidual transformation and BLS/blastocyst expansion.
  
  
  CONCLUSIONS
  KLF12 impairs endometrial decidualization by transcriptionally repressing Nur77, and Nur77 overexpression reverses the poor decidual response of hESCs in RIF patients.
authors.affiliation: Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China.
authors.forename: Chenyang
authors.initials: C
authors.lastname: Huang
authors.affiliation: Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China.
authors.forename: Ruiwei
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China.
authors.forename: Xi
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xing
authors.affiliation: Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Ding
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Sun
authors.affiliation: Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China. yanguijun55@163.com.
authors.forename: Guijun
authors.initials: G
authors.lastname: Yan
authors.affiliation: Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China. stevensunz@163.com.|Collaborative Innovation Platform for Reproductive Biology and Technology of Nanjing University Medical School, Nanjing, 210008, People's Republic of China. stevensunz@163.com.
authors.forename: Haixiang
authors.initials: H
authors.lastname: Sun
mesh_terms: D000328:Adult; D000818:Animals; D001755:Blastocyst / Q000166:cytology; D015153:Blotting, Western; D002478:Cells, Cultured; D018920:Coculture Techniques; D003656:Decidua / Q000378:metabolism*; D010064:Embryo Implantation; D004717:Endometrium / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007247:Infertility, Female / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism
chemical_list: C436492:KLF12 protein, human; D051741:Kruppel-Like Transcription Factors; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1
keywords: Decidualization; KLF12; Nur77; Recurrent implantation failure