Chiu Yueh Ho, Chen Hungwen
Graduate Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan.
Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan.
Sci Rep. 2016 Feb 22;6:21630. doi: 10.1038/srep21630.
Development of human placenta involves the invasion of trophoblast cells from anchoring villi into the maternal decidua. Placental transcription factor GCM1 regulates trophoblast cell invasion via transcriptional activation of HtrA4 gene, which encodes a serine protease enzyme. The GATA3 transcription factor regulates trophoblast cell differentiation and is highly expressed in invasive murine trophoblast giant cells. The regulation of trophoblastic invasion by GCM1 may involve novel cellular factors. Here we show that GATA3 interacts with GCM1 and inhibits its activity to suppress trophoblastic invasion. Immunohistochemistry demonstrates that GATA3 and GCM1 are coexpressed in villous cytotrophoblast cells, syncytiotrophoblast layer, and extravillous trophoblast cells of human placenta. Interestingly, GATA3 interacts with GCM1, but not the GCM2 homologue, through the DNA-binding domain and first transcriptional activation domain in GCM1 and the transcriptional activation domains and zinc finger 1 domain in GATA3. While GATA3 did not affect DNA-binding activity of GCM1, it suppressed transcriptional activity of GCM1 and therefore HtrA4 promoter activity. Correspondingly, GATA3 knockdown elevated HtrA4 expression in BeWo and JEG-3 trophoblast cell lines and enhanced the invasion activities of both lines. This study uncovered a new GATA3 function in placenta as a negative regulator of GCM1 activity and trophoblastic invasion.
人类胎盘的发育涉及到来自固定绒毛的滋养层细胞侵入母体蜕膜。胎盘转录因子GCM1通过编码丝氨酸蛋白酶的HtrA4基因的转录激活来调节滋养层细胞的侵袭。GATA3转录因子调节滋养层细胞分化，并在侵袭性小鼠滋养层巨细胞中高表达。GCM1对滋养层侵袭的调节可能涉及新的细胞因子。在这里，我们表明GATA3与GCM1相互作用并抑制其活性以抑制滋养层侵袭。免疫组织化学表明，GATA3和GCM1在人胎盘的绒毛细胞滋养层细胞、合体滋养层和绒毛外滋养层细胞中共表达。有趣的是，GATA3通过GCM1中的DNA结合结构域和第一个转录激活结构域以及GATA3中的转录激活结构域和锌指1结构域与GCM1相互作用，但不与GCM2同源物相互作用。虽然GATA3不影响GCM1的DNA结合活性，但它抑制了GCM1的转录活性，从而抑制了HtrA4启动子活性。相应地，在BeWo和JEG-3滋养层细胞系中敲低GATA3可提高HtrA4的表达，并增强这两种细胞系的侵袭活性。这项研究揭示了GATA3在胎盘中作为GCM1活性和滋养层侵袭的负调节因子的新功能。
