Three mechanisms in the pathogenesis of pre-eclampsia suggested by over-represented transcription factor-binding sites detected with comparative promoter analysis

Abstract

Microarray studies generating lists of genes with altered expression in placentas from pregnancies complicated with pre-eclampsia (PE) have so far been published in several different studies. Working under the assumption that altered gene expression in PE may be the result of altered expression of regulatory transcription factors (TFs), we looked for over-represented TF-binding sites (TFBSs)-which indicate the involvement of TFs in gene regulatory networks-in lists of genes (n = 143) compiled in these studies. We compared the prevalence of TFBSs in the promoter regions of 68 genes with the background prevalence of TFBSs in promoters of the human genome. The prevalence of the E47, sterol regulatory element binding protein (SREBP) and NFKB-p50 TFBSs was higher (P < 0.005) in the promoter sequences of the PE gene lists than in the background model. Each of these TFBSs could be implicated in the development of PE. The E47 protein is an E-protein or basic helix-loop-helix (bHLH) TF. Data support the role of bHLHs in the differentiation of placental tissue. SREBP-1, a lipid-sensing sterol regulatory element-binding protein, is a critical regulator of fatty acid homeostasis in the placenta. The target genes of NFKB-p50 determine inflammatory response, and aberrant cytokine homeostasis is a further sign of PE. These TFs may provide an insight into the pathogenesis of the disease.