A Positive Feedback Loop between Glial Cells Missing 1 and Human Chorionic Gonadotropin (hCG) Regulates Placental hCGβ Expression and Cell Differentiation.
Human chorionic gonadotropin (hCG) is composed of a common α subunit and a placenta-specific β subunit. Importantly, hCG is highly expressed in the differentiated and multinucleated syncytiotrophoblast, which is formed via trophoblast cell fusion and stimulated by cyclic AMP (cAMP). Although the ubiquitous activating protein 2 (AP2) transcription factors TFAP2A and TFAP2C may regulate hCGβ expression, it remains unclear how cAMP stimulates placenta-specific hCGβ gene expression and trophoblastic differentiation. Here we demonstrated that the placental transcription factor glial cells missing 1 (GCM1) binds to a highly conserved promoter region in all six hCGβ paralogues by chromatin immunoprecipitation-on-chip (ChIP-chip) analyses. We further showed that cAMP stimulates GCM1 and the CBP coactivator to activate the hCGβ promoter through a GCM1-binding site (GBS1), which also constitutes a previously identified AP2 site. Given that TFAP2C may compete with GCM1 for GBS1, cAMP enhances the association between the hCGβ promoter and GCM1 but not TFAP2C. Indeed, the hCG-cAMP-protein kinase A (PKA) signaling pathway also stimulates Ser269 and Ser275 phosphorylation of GCM1, which recruits CBP to mediate GCM1 acetylation and stabilization. Consequently, hCG stimulates the expression of GCM1 target genes, including the fusogenic protein syncytin-1, to promote placental cell fusion. Our study reveals a positive feedback loop between GCM1 and hCG regulating placental hCGβ expression and cell differentiation.
Graduate Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei, Taiwan College of Medicine, Taipei Medical University, Taipei, Taiwan.
Mei-Leng
ML
Cheong
Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei, Taiwan.
Liang-Jie
LJ
Wang
Graduate Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
Pei-Yun
PY
Chuang
Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei, Taiwan.
Ching-Wen
CW
Chang
Department of Biotechnology, Ming Chuan University, Tao-Yuan, Taiwan.
Yun-Shien
YS
Lee
Graduate Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
Hsiao-Fan
HF
Lo
Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei, Taiwan College of Medicine, Taipei Medical University, Taipei, Taiwan.
Ming-Song
MS
Tsai
Graduate Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei, Taiwan hwchen@gate.sinica.edu.tw.
Hungwen
H
Chen
D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D006063:Chorionic Gonadotropin / Q000235:genetics / Q000378:metabolism*; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D009457:Neuroglia / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D006063:Chorionic Gonadotropin; D018997:Chorionic Gonadotropin, beta Subunit, Human; D004268:DNA-Binding Proteins; C491089:GCM1 protein, human; C101631:Gcm1 protein, mouse; D009479:Neuropeptides; D009687:Nuclear Proteins; D014157:Transcription Factors