Limits...
Integrative transcriptome analysis reveals dysregulation of canonical cancer molecular pathways in placenta leading to preeclampsia.

Moslehi R, Mills JL, Signore C, Kumar A, Ambroggio X, Dzutsev A - Sci Rep (2013)

Bottom Line: To identify the underlying mechanisms, we conducted the current integrative analysis of several relevant transcriptome data sources.Our meta-analysis revealed downregulation of TFIIH subunits in preeclamptic placentas.Our overall integrative analysis suggested that, in the presence of hypoxia and oxidative stress, EGFR signaling deficiency, which can be caused by TFIIH impairment as well as by other mechanisms, results in ATF3 upregulation, inducing mediators of clinical symptoms of preeclampsia such as FLT1 and ENG.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, NY 12144, USA. rmoslehi@albany.edu

ABSTRACT
We previously suggested links between specific XPD mutations in the fetal genome and the risk of placental maldevelopment and preeclampsia, possibly due to impairment of Transcription Factor (TF)IIH-mediated functions in placenta. To identify the underlying mechanisms, we conducted the current integrative analysis of several relevant transcriptome data sources. Our meta-analysis revealed downregulation of TFIIH subunits in preeclamptic placentas. Our overall integrative analysis suggested that, in the presence of hypoxia and oxidative stress, EGFR signaling deficiency, which can be caused by TFIIH impairment as well as by other mechanisms, results in ATF3 upregulation, inducing mediators of clinical symptoms of preeclampsia such as FLT1 and ENG. EGFR- and ATF3-dependent pathways play prominent roles in cancer development. We propose that dysregulation of these canonical cancer molecular pathways occurs in preeclampsia and delineate the relevance of TFIIH, providing etiologic clues which could eventually translate into a therapeutic approach.

Show MeSH

Related in: MedlinePlus

Transcriptome analysis of XPDTTD fibroblasts.Panel (a). Heatmap constructed using 136 genes downregulated in preeclampsia meta-analysis demonstrating the 34 genes significantly-downregulated in XPDTTD Fibroblasts versus XPDTTD Fibroblasts transfected with wild-type XPD. Panel (b). GSEA of XPDTTD Fibroblasts with respect to genes downregulated in preeclampsia. The analysis demonstrates significant correlation (q < 0.1, Enrichment Score = 0.15) between many genes downregulated in preeclampsia and in XPDTTD Fibroblasts. Panel (c). GO analysis of gene signature of XPDTTD Fibroblasts using network visualization and analysis tool (as described in the Methods). Size of the nodes is inversely proportional to the p-values. Groups identified using clustering algorithm; most common GO terms are listed next to the node groups. Panel (d). Transcription factor analysis of the genes downregulated in XPDTTD fibroblasts using network visualization and analysis tool. Groups identified using clustering algorithm; most common transcription factors are listed next to the nodes. Size of the nodes is inversely proportional to the p-values.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3757356&req=5

f4: Transcriptome analysis of XPDTTD fibroblasts.Panel (a). Heatmap constructed using 136 genes downregulated in preeclampsia meta-analysis demonstrating the 34 genes significantly-downregulated in XPDTTD Fibroblasts versus XPDTTD Fibroblasts transfected with wild-type XPD. Panel (b). GSEA of XPDTTD Fibroblasts with respect to genes downregulated in preeclampsia. The analysis demonstrates significant correlation (q < 0.1, Enrichment Score = 0.15) between many genes downregulated in preeclampsia and in XPDTTD Fibroblasts. Panel (c). GO analysis of gene signature of XPDTTD Fibroblasts using network visualization and analysis tool (as described in the Methods). Size of the nodes is inversely proportional to the p-values. Groups identified using clustering algorithm; most common GO terms are listed next to the node groups. Panel (d). Transcription factor analysis of the genes downregulated in XPDTTD fibroblasts using network visualization and analysis tool. Groups identified using clustering algorithm; most common transcription factors are listed next to the nodes. Size of the nodes is inversely proportional to the p-values.

Mentions: Global gene expression profiling of XPDTTD fibroblasts (i.e., fibroblasts from TTD patients with mutations in XPD) versus XPDTTD fibroblasts transfected with the wild type XPD in a dataset obtained through personal communications28 identified 660 genes differentially-regulated in XPDTTD fibroblasts. The majority of the 314 upregulated and 346 downregulated genes were involved in cell cycle and growth (data not shown). Similar to the previous analysis of hypoxic trophoblasts, we performed GSEA using genes upregulated and downregulated in preeclampsia to detect similarities between gene signatures of XPDTTD mutant cells and those of preeclampsia. We found that genes downregulated in XPDTTD mutant cells had significant similarity (q < 0.1) with those downregulated in preeclampsia (Figures 4a and 4b), suggesting potential similarities between downstream pathways affected by XPD mutations and pathways affected in preeclampsia.


Integrative transcriptome analysis reveals dysregulation of canonical cancer molecular pathways in placenta leading to preeclampsia.

Moslehi R, Mills JL, Signore C, Kumar A, Ambroggio X, Dzutsev A - Sci Rep (2013)

Transcriptome analysis of XPDTTD fibroblasts.Panel (a). Heatmap constructed using 136 genes downregulated in preeclampsia meta-analysis demonstrating the 34 genes significantly-downregulated in XPDTTD Fibroblasts versus XPDTTD Fibroblasts transfected with wild-type XPD. Panel (b). GSEA of XPDTTD Fibroblasts with respect to genes downregulated in preeclampsia. The analysis demonstrates significant correlation (q < 0.1, Enrichment Score = 0.15) between many genes downregulated in preeclampsia and in XPDTTD Fibroblasts. Panel (c). GO analysis of gene signature of XPDTTD Fibroblasts using network visualization and analysis tool (as described in the Methods). Size of the nodes is inversely proportional to the p-values. Groups identified using clustering algorithm; most common GO terms are listed next to the node groups. Panel (d). Transcription factor analysis of the genes downregulated in XPDTTD fibroblasts using network visualization and analysis tool. Groups identified using clustering algorithm; most common transcription factors are listed next to the nodes. Size of the nodes is inversely proportional to the p-values.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757356&req=5

f4: Transcriptome analysis of XPDTTD fibroblasts.Panel (a). Heatmap constructed using 136 genes downregulated in preeclampsia meta-analysis demonstrating the 34 genes significantly-downregulated in XPDTTD Fibroblasts versus XPDTTD Fibroblasts transfected with wild-type XPD. Panel (b). GSEA of XPDTTD Fibroblasts with respect to genes downregulated in preeclampsia. The analysis demonstrates significant correlation (q < 0.1, Enrichment Score = 0.15) between many genes downregulated in preeclampsia and in XPDTTD Fibroblasts. Panel (c). GO analysis of gene signature of XPDTTD Fibroblasts using network visualization and analysis tool (as described in the Methods). Size of the nodes is inversely proportional to the p-values. Groups identified using clustering algorithm; most common GO terms are listed next to the node groups. Panel (d). Transcription factor analysis of the genes downregulated in XPDTTD fibroblasts using network visualization and analysis tool. Groups identified using clustering algorithm; most common transcription factors are listed next to the nodes. Size of the nodes is inversely proportional to the p-values.
Mentions: Global gene expression profiling of XPDTTD fibroblasts (i.e., fibroblasts from TTD patients with mutations in XPD) versus XPDTTD fibroblasts transfected with the wild type XPD in a dataset obtained through personal communications28 identified 660 genes differentially-regulated in XPDTTD fibroblasts. The majority of the 314 upregulated and 346 downregulated genes were involved in cell cycle and growth (data not shown). Similar to the previous analysis of hypoxic trophoblasts, we performed GSEA using genes upregulated and downregulated in preeclampsia to detect similarities between gene signatures of XPDTTD mutant cells and those of preeclampsia. We found that genes downregulated in XPDTTD mutant cells had significant similarity (q < 0.1) with those downregulated in preeclampsia (Figures 4a and 4b), suggesting potential similarities between downstream pathways affected by XPD mutations and pathways affected in preeclampsia.

Bottom Line: To identify the underlying mechanisms, we conducted the current integrative analysis of several relevant transcriptome data sources.Our meta-analysis revealed downregulation of TFIIH subunits in preeclamptic placentas.Our overall integrative analysis suggested that, in the presence of hypoxia and oxidative stress, EGFR signaling deficiency, which can be caused by TFIIH impairment as well as by other mechanisms, results in ATF3 upregulation, inducing mediators of clinical symptoms of preeclampsia such as FLT1 and ENG.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, NY 12144, USA. rmoslehi@albany.edu

ABSTRACT
We previously suggested links between specific XPD mutations in the fetal genome and the risk of placental maldevelopment and preeclampsia, possibly due to impairment of Transcription Factor (TF)IIH-mediated functions in placenta. To identify the underlying mechanisms, we conducted the current integrative analysis of several relevant transcriptome data sources. Our meta-analysis revealed downregulation of TFIIH subunits in preeclamptic placentas. Our overall integrative analysis suggested that, in the presence of hypoxia and oxidative stress, EGFR signaling deficiency, which can be caused by TFIIH impairment as well as by other mechanisms, results in ATF3 upregulation, inducing mediators of clinical symptoms of preeclampsia such as FLT1 and ENG. EGFR- and ATF3-dependent pathways play prominent roles in cancer development. We propose that dysregulation of these canonical cancer molecular pathways occurs in preeclampsia and delineate the relevance of TFIIH, providing etiologic clues which could eventually translate into a therapeutic approach.

Show MeSH
Related in: MedlinePlus