Nucleotide excision repair/transcription gene defects in the fetus and impaired TFIIH-mediated function in transcription in placenta leading to preeclampsia.

Roxana Moslehi,Vijayaraj Nagarajan,Anil Kumar,Xavier Ambroggio,Amiran Dzutsev

doi:10.1186/1471-2164-15-373

Abstract

BackgroundPreeclampsia is a significant cause of maternal and fetal mortality and morbidity worldwide. We previously reported associations between trichothiodystrophy (TTD) nucleotide excision repair (NER) and transcription gene mutations in the fetus and the risk of gestational complications including preeclampsia. TTD NER/transcription genes, XPD, XPB and TTD-A, code for subunits of Transcription Factor (TF)IIH. Interpreting XPD mutations in the context of available biochemical data led us to propose adverse effects on CDK-activating kinase (CAK) subunit of TFIIH and TFIIH-mediated functions as a relevant mechanism in preeclampsia. In order to gain deeper insight into the underlying biologic mechanisms involving TFIIH-mediated functions in placenta, we analyzed NER/transcription and global gene expression profiles of normal and preeclamptic placentas and studied gene regulatory networks.ResultsWe found high expression of TTD NER/transcription genes in normal human placenta, above the mean of their expression in all organs. XPD and XPB were consistently expressed from 14 to 40 weeks gestation while expression of TTD-A was strongly negatively correlated (r = -0.7, P < 0.0001) with gestational age. Analysis of gene expression patterns of placentas from a case-control study of preeclampsia using Algorithm for Reconstruction of Accurate Cellular Networks (ARACNE) revealed GTF2E1, a component of TFIIE which modulates TFIIH, among major regulators of differentially-expressed genes in preeclampsia. The basal transcription pathway was among the largest dysregulated protein-protein interaction networks in this preeclampsia dataset. Within the basal transcription pathway, significantly down-regulated genes besides GTF2E1 included those coding for the CAK complex of TFIIH, namely CDK7, CCNH, and MNAT1. Analysis of other relevant gene expression and gene regulatory network data also underscored the involvement of transcription pathways and identified JUNB and JUND (components of transcription factor AP-1) as transcription regulators of the network involving the TTD genes, GTF2E1, and selected gene regulators implicated in preeclampsia.ConclusionsOur results indicate that TTD NER/transcription genes are expressed in placenta during gestational periods critical to preeclampsia development. Our overall findings suggest that impairment of TFIIH-mediated function in transcription in placenta is a likely mechanism leading to preeclampsia and provide etiologic clues which may be translated into therapeutic and preventive measures.

Highlights

Preeclampsia is a significant cause of maternal and fetal mortality and morbidity worldwide
Preeclampsia is identified clinically as hypertension that first occurs after 20 weeks gestation [1] but may be due to processes which develop earlier, genes relevant to preeclampsia would be expected to be expressed during the critical gestational periods of ≤20 weeks gestation as well
In order to infer the relevance of the TTD nucleotide excision repair (NER)/ transcription genes to processes which lead to preeclampsia, we conducted time-course analysis of the three TTD NER/ transcription gene expression patterns in normal placenta from 14-40 weeks gestation in GSE5999 [22]

Summary

Introduction

Preeclampsia is a significant cause of maternal and fetal mortality and morbidity worldwide. We previously reported associations between trichothiodystrophy (TTD) nucleotide excision repair (NER) and transcription gene mutations in the fetus and the risk of gestational complications including preeclampsia. TTD NER/transcription genes, XPD, XPB and TTD-A, code for subunits of Transcription Factor (TF)IIH. We first conceived the hypothesis for the association between nucleotide excision repair (NER) and transcription gene abnormalities in the fetal genome and risk of gestational complications in 2003 based on our clinical observations and systematic genetic epidemiologic investigations in families with trichothiodystrophy (TTD) [8]. TTD is a rare (affected frequency of 1 in 106) recessive disorder [9] caused by mutations in XPD (ERCC2), XPB (ERCC3), and TTD-A (GTF2H5), which encode three of the subunits of transcription factor (TF)IIH, as well as in TTDN1 [9,10,11]. Mutations in XPB and XPD can cause other rare recessive DNA repair disorders such as xeroderma pigmentosum (XP) [9,12]

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