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.2013 Dec 12;1(3):1017.

MTA1 and MTA3 Regulate HIF1a Expression in Hypoxia-Treated Human Trophoblast Cell Line HTR8/Svneo

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MTA1 and MTA3 Regulate HIF1a Expression in Hypoxia-Treated Human Trophoblast Cell Line HTR8/Svneo

Kai Wang et al. Med J Obstet Gynecol..

Abstract

Hypoxia plays an important role in placental trophoblast differentiation and function during early pregnancy. Hypoxia-inducible factor 1 alpha (HIF1a) is known to regulate cellular adaption to hypoxic conditions. However, our current understanding of the role of HIF1a in trophoblast physiology is far from complete. Metastasis Associated Protein 1 and 3 (MTA1 and MTA3) are components of the Nucleosome Remodeling and Deacetylase (NuRD) complex, a chromatin remodeling complex, and are highly expressed in term placental trophoblasts. However, the role of MTA1 and MTA3 in the hypoxic placental environment of early pregnancy is unknown. In the present study, we examined the association among MTA1, MTA3 and HIF1a expression under hypoxic conditions in trophoblasts both in vivo and in vitro. We first investigated the localization of MTA1 and MTA3 with HIF1a expression in the placental trophoblast of 1st trimester placenta via immunohistochemistry. Our data reveals that under physiologically hypoxic environment, MTA1 and MTA3 along with HIF1a are highly expressed by villous trophoblasts. Next, we investigated the effect of hypoxia on these genes in vitro using the first trimester-derived HTR8/SVneo cell line and observed up-regulation of MTA1 and MTA3 as well as HIF1a protein following hypoxia treatment. To investigate the direct effect of MTA1 and MTA3 upon HIF1a, we over-expressed MTA1 and MTA3 genes in HTR8/SVneo cells respectively and examined protein levels of HIF1a via Western blot as well as HIF1a target gene expression using a luciferase assay driven by a hypoxia-response element promoter (HRE-luciferase). We found that over-expressions of MTA1 and MTA3 up-regulate both HIF1a protein level and HRE-luciferase activity under hypoxic condition. In summary, both MTA1 and MTA3 are induced by hypoxia and up-regulate HIF1a expression and HIF1a target gene expression in trophoblasts. These data suggest that MTA1 and MTA3 play critical roles in trophoblast function and differentiation during early pregnancy.

Keywords: Chromatin remodeling; Hypoxia; Trophoblast.

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Conflict of interest statement

Declaration of interest

There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Figures

Figure 1
Figure 1
Co-localization of MTA1, MTA3 and HIF1a in 1st trimester placenta and hypoxia treated HTR8/SVneo cells. A. Expressions of MTA1, MTA3, hCG and HIF1a in villous trophoblasts of 9-week placenta detected by IHC. Yellow arrows indicate cytotrophoblasts and red arrows indicate syncytiotrophoblasts. B. Expressions of MTA1, MTA3, HIF1a and Actin (a typical cytoplasmic marker protein) in the cytoplasm (C) and nuclei (N) of HTR8/SVneo following hypoxia treatment (1%O2) as detected by Western blot.
Figure 2
Figure 2
Hypoxia induces expressions of MTA1, MTA3 and HIF1a in HTR8/SVneo cells as detected by western blot. The representative western blot results are shown in left panel, and their quantified results (normalized by Actin) are demonstrated in right panel.
Figure 3
Figure 3
Up-regulation of HIF1a in protein levels and HRE-luciferase activity levels by MTA1 and MTA3 in HTR8/SVneo cells as detected by Western blot and HRE-luciferase assay, respectively. A. Expressions of V5 tagged MTA1 and MTA3 (MTA1V5 and MTA3V5), HIF1a and Actin were detected in MTA1V5-, MTA3V5- overexpressing and control HTR8/SVneo cells under hypoxic (1% O2) and normoxic (20% O2) conditions. MTA1V5 and MTA3V5 proteins were detected by V5 antibody. B. Relative HRE-luciferase activity levels (normalized using the internal control pRen-TK). Asterisk represents the statistical significance (p< 0.05) compared with the control. Results are representative of 3 biological repeats.
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