GXB: Hypoxia induced HIF-1/HIF-2 activity alters trophoblast transcriptional regulation and promotes invasion

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Description

Hypoxia induced HIF-1/HIF-2 activity alters trophoblast transcriptional regulation and promotes invasion - GSE65271

Purpose

Reduced or absent cytotrophoblast invasion of the maternal uterine spiral arteries is a common clinical finding in studies of pregnancies complicated by preeclampsia, suggesting that the mechanisms behind invasion of these cells is perturbed. The placenta initially develops in a low oxygen environment of 1-2% oxygen until after the 10th week of pregnancy. During this time oxygen concentration exerts a major influence over trophoblast activity and, in vitro, hypoxia inducible factors are proposed to be one of many key regulators of first trimester trophoblast behaviour. We used a global gene expression microarray approach to identify signalling pathways involved in invasion of the first trimester trophoblast cell line HTR8/SVneo under hypoxic conditions where HIF-1 was active. Additionally, first trimester placental samples from different gestational age groups were labelled with anti HIF-1 and HIF-2 to evaluate whether HIFs are differentially expressed and localised across the period of development characterised by hypoxia (6-8 weeks) and maternal blood perfusion (10-12 weeks). Eighty-eight genes were differentially expressed between cells cultured in 1% oxygen (where HIF-1 was localised to the nucleus) and 5% oxygen (where HIF-1 was cytoplasmic). 65% of the genes were predicted to contain HIF-1?:ARNT transcription factor binding sites. Increased nuclear localisation of HIF-1? was seen in extravillous cytotrophoblasts in early first trimester compared with late, while cellular expression of HIF-2? in the villous stroma was higher in late first trimester. While HIFs and their downstream targets are clearly induced in trophoblasts during early placental development, and in vitro hypoxic conditions, the mechanism and pathways by which invasion is increased under hypoxic conditions is not clear from the gene expression profile. Further insight beyond the transcription level is required to fully understand this complex phenomenon.

Experimental Design

In this study we sought to elucidate the role of hypoxia-inducible genes in HTR8/SVneo invasiveness by performing global gene expression analysis under conditions where HIF-1? was predicted to be active (1% O2) and inactive (5% O2, physiological normoxia). Ambient oxygen standard culture conditions (20% O2) were also included to evaluate the effect of using 5% oxygen rather than 20% as a representation of normoxia. Particular attention was paid to the role of HIFs, which mediate the effects of hypoxia on the cell, as a key regulator of gene expression. Differential HIF-1 localization in HTR8/SVneo was confirmed under our culture conditions, and in first trimester placenta sections of different gestational ages to confirm that HIF is highly expressed in trophoblasts during different stages of differentiation. Microarray experiments were performed with and without growth factor reduced Matrigel; cells cultured on Matrigel representing an extravillous, endovascular-like phenotype of HTR8/SVneo (Highet et al., 2012) while HTR8/Svneo cultured on plastic are believed to be a phenotype resembling cells of the proximal region of cytotrophoblast columns (Kilburn et al., 2000).

Platform

Illumina HumanHT-12 v4

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Hypoxia induced HIF-1/HIF-2 activity alters trophoblast transcriptional regulation and promotes invasion - GSE65271

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