Abstract
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.
Highlights
The GATA family of transcription factors is composed of six members, GATA1-6, with structural features of two N-terminal transactivation domains (TADs) and two carboxyl-terminal zinc fingers[9]
We demonstrate that GCM1 and GATA3 interact with each other through the N-terminal DNA-binding domain (DBD) and the first TAD in GCM1 and the TADs and zinc finger 1 domain in GATA3
Several potential GATA3 sites were found in the first 1 kb region of HtrA4 promoter, their involvement in the suppression of HtrA4 gene expression by GATA3 was not detected in the present study
Summary
The GATA family of transcription factors is composed of six members, GATA1-6, with structural features of two N-terminal transactivation domains (TADs) and two carboxyl-terminal zinc fingers[9]. GATA3 is abundantly expressed in the TG cells of mouse placenta Along this line, GATA3 has been shown to regulate trophoblast stem cell differentiation and placental lactogen I and proliferin gene expression[11]. GATA3 has been shown to regulate trophoblast stem cell differentiation and placental lactogen I and proliferin gene expression[11] As both GCM1 and GATA3 are key placental factors, we investigate the possibility that both factors may interact with each other to regulate placental cell activity. We demonstrate that GATA3 physically interacts with GCM1, but not GCM2 Both factors are expressed in CTB cells, the STB layer, and EVT cells of first-trimester and term human placentas. Our results reveal a novel function of GATA3 in control of trophoblast cell invasion through downregulation of GCM1 activity and HtrA4 expression
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