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Extensive shift in placental transcriptome profile in preeclampsia and placental origin of adverse pregnancy outcomes.

Sõber S, Reiman M, Kikas T, Rull K, Inno R, Vaas P, Teesalu P, Marti JM, Mattila P, Laan M - Sci Rep (2015)

Bottom Line: The transcriptome of LO-PE placentas was clearly distinct, showing statistically significant (after FDR) expressional disturbances for hundreds of genes.Taqman RT-qPCR validation of 45 genes in an extended sample (n = 24/group) provided concordant results.The dataset represent a rich catalogue for potential biomarkers and therapeutic targets.

View Article: PubMed Central - PubMed

Affiliation: Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia.

ABSTRACT
One in five pregnant women suffer from gestational complications, prevalently driven by placental malfunction. Using RNASeq, we analyzed differential placental gene expression in cases of normal gestation, late-onset preeclampsia (LO-PE), gestational diabetes (GD) and pregnancies ending with the birth of small-for-gestational-age (SGA) or large-for-gestational-age (LGA) newborns (n = 8/group). In all groups, the highest expression was detected for small noncoding RNAs and genes specifically implicated in placental function and hormonal regulation. The transcriptome of LO-PE placentas was clearly distinct, showing statistically significant (after FDR) expressional disturbances for hundreds of genes. Taqman RT-qPCR validation of 45 genes in an extended sample (n = 24/group) provided concordant results. A limited number of transcription factors including LRF, SP1 and AP2 were identified as possible drivers of these changes. Notable differences were detected in differential expression signatures of LO-PE subtypes defined by the presence or absence of intrauterine growth restriction (IUGR). LO-PE with IUGR showed higher correlation with SGA and LO-PE without IUGR with LGA placentas. Whereas changes in placental transcriptome in SGA, LGA and GD cases were less prominent, the overall profiles of expressional disturbances overlapped among pregnancy complications providing support to shared placental responses. The dataset represent a rich catalogue for potential biomarkers and therapeutic targets.

No MeSH data available.


Related in: MedlinePlus

High concordance in placental gene expression changes in alternative scenarios of complicated compared to normal pregnancy.(a) Correlation plots for the fold changes of the highest ranked genes in the differential expression testing in each pregnancy complication compared to normal pregnancy (DESeq analysis). For each pairwise analysis of gestational complications, the lists of top-200 genes (circles) were united and plotted at the x,y-plane, where the axes correspond to the log2(fold changes) in the two groups. Red circles represent genes, which are shared between the top gene lists. The linear regression line along with correlation coefficient R2 and statistical significance is given. (b) Venn diagram for the shared fraction of the highest ranked genes in differential expression testing in alternative pregnancy complications. The number and gene list in each intersection are given. PE, preeclampsia, GD, gestational diabetes, SGA and LGA, small- and large-for-gestational-age newborns.
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f5: High concordance in placental gene expression changes in alternative scenarios of complicated compared to normal pregnancy.(a) Correlation plots for the fold changes of the highest ranked genes in the differential expression testing in each pregnancy complication compared to normal pregnancy (DESeq analysis). For each pairwise analysis of gestational complications, the lists of top-200 genes (circles) were united and plotted at the x,y-plane, where the axes correspond to the log2(fold changes) in the two groups. Red circles represent genes, which are shared between the top gene lists. The linear regression line along with correlation coefficient R2 and statistical significance is given. (b) Venn diagram for the shared fraction of the highest ranked genes in differential expression testing in alternative pregnancy complications. The number and gene list in each intersection are given. PE, preeclampsia, GD, gestational diabetes, SGA and LGA, small- and large-for-gestational-age newborns.

Mentions: In order to investigate potential shared placental pathophysiology of pregnancy complications, we compared the estimated differential expression effects for the top-200 genes from the RNA-Seq analysis of LO-PE, GD, SGA and LGA placentas, irrespective of statistical significance. The highest concordance in gene expression disturbances compared to normal pregnancy was detected for SGA and LO-PE placentas, correlation between the log2(fold change) was R2 = 0.70 (linear regression, P = 2.71×10−96; Fig. 5a). All genes with increased placental transcript levels in PE were concordantly up-regulated in SGA and only a few genes down-regulated in PE were not affected in SGA. Strong correlation between the effects of top-200 genes was also identified for LO-PE and LGA (R2 = 0.60; P = 4.99 × 10−69) placentas. Unexpectedly, we also detected correlation between the expression changes of the top-200 genes in the SGA and LGA placentas compared to normal pregnancy (R2 = 0.45; P = 1.99 × 10−49), possibly indicative to placental adaptations in unfavorable conditions. Among these, 65 genes exhibited opposite effect directions, including well-acknowledged markers of aberrant placental development (LEP, FLT, ENG, HTRA4, SH3PXD2A) (Supplementary Table S4). Gene expression profile of top-200 genes in GD placentas exhibited a less pronounced overlap with other pathologies (R2 = 0.13–0.29; P ≤ 2.21 × 10−12; Fig. 5a).


Extensive shift in placental transcriptome profile in preeclampsia and placental origin of adverse pregnancy outcomes.

Sõber S, Reiman M, Kikas T, Rull K, Inno R, Vaas P, Teesalu P, Marti JM, Mattila P, Laan M - Sci Rep (2015)

High concordance in placental gene expression changes in alternative scenarios of complicated compared to normal pregnancy.(a) Correlation plots for the fold changes of the highest ranked genes in the differential expression testing in each pregnancy complication compared to normal pregnancy (DESeq analysis). For each pairwise analysis of gestational complications, the lists of top-200 genes (circles) were united and plotted at the x,y-plane, where the axes correspond to the log2(fold changes) in the two groups. Red circles represent genes, which are shared between the top gene lists. The linear regression line along with correlation coefficient R2 and statistical significance is given. (b) Venn diagram for the shared fraction of the highest ranked genes in differential expression testing in alternative pregnancy complications. The number and gene list in each intersection are given. PE, preeclampsia, GD, gestational diabetes, SGA and LGA, small- and large-for-gestational-age newborns.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4542630&req=5

f5: High concordance in placental gene expression changes in alternative scenarios of complicated compared to normal pregnancy.(a) Correlation plots for the fold changes of the highest ranked genes in the differential expression testing in each pregnancy complication compared to normal pregnancy (DESeq analysis). For each pairwise analysis of gestational complications, the lists of top-200 genes (circles) were united and plotted at the x,y-plane, where the axes correspond to the log2(fold changes) in the two groups. Red circles represent genes, which are shared between the top gene lists. The linear regression line along with correlation coefficient R2 and statistical significance is given. (b) Venn diagram for the shared fraction of the highest ranked genes in differential expression testing in alternative pregnancy complications. The number and gene list in each intersection are given. PE, preeclampsia, GD, gestational diabetes, SGA and LGA, small- and large-for-gestational-age newborns.
Mentions: In order to investigate potential shared placental pathophysiology of pregnancy complications, we compared the estimated differential expression effects for the top-200 genes from the RNA-Seq analysis of LO-PE, GD, SGA and LGA placentas, irrespective of statistical significance. The highest concordance in gene expression disturbances compared to normal pregnancy was detected for SGA and LO-PE placentas, correlation between the log2(fold change) was R2 = 0.70 (linear regression, P = 2.71×10−96; Fig. 5a). All genes with increased placental transcript levels in PE were concordantly up-regulated in SGA and only a few genes down-regulated in PE were not affected in SGA. Strong correlation between the effects of top-200 genes was also identified for LO-PE and LGA (R2 = 0.60; P = 4.99 × 10−69) placentas. Unexpectedly, we also detected correlation between the expression changes of the top-200 genes in the SGA and LGA placentas compared to normal pregnancy (R2 = 0.45; P = 1.99 × 10−49), possibly indicative to placental adaptations in unfavorable conditions. Among these, 65 genes exhibited opposite effect directions, including well-acknowledged markers of aberrant placental development (LEP, FLT, ENG, HTRA4, SH3PXD2A) (Supplementary Table S4). Gene expression profile of top-200 genes in GD placentas exhibited a less pronounced overlap with other pathologies (R2 = 0.13–0.29; P ≤ 2.21 × 10−12; Fig. 5a).

Bottom Line: The transcriptome of LO-PE placentas was clearly distinct, showing statistically significant (after FDR) expressional disturbances for hundreds of genes.Taqman RT-qPCR validation of 45 genes in an extended sample (n = 24/group) provided concordant results.The dataset represent a rich catalogue for potential biomarkers and therapeutic targets.

View Article: PubMed Central - PubMed

Affiliation: Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia.

ABSTRACT
One in five pregnant women suffer from gestational complications, prevalently driven by placental malfunction. Using RNASeq, we analyzed differential placental gene expression in cases of normal gestation, late-onset preeclampsia (LO-PE), gestational diabetes (GD) and pregnancies ending with the birth of small-for-gestational-age (SGA) or large-for-gestational-age (LGA) newborns (n = 8/group). In all groups, the highest expression was detected for small noncoding RNAs and genes specifically implicated in placental function and hormonal regulation. The transcriptome of LO-PE placentas was clearly distinct, showing statistically significant (after FDR) expressional disturbances for hundreds of genes. Taqman RT-qPCR validation of 45 genes in an extended sample (n = 24/group) provided concordant results. A limited number of transcription factors including LRF, SP1 and AP2 were identified as possible drivers of these changes. Notable differences were detected in differential expression signatures of LO-PE subtypes defined by the presence or absence of intrauterine growth restriction (IUGR). LO-PE with IUGR showed higher correlation with SGA and LO-PE without IUGR with LGA placentas. Whereas changes in placental transcriptome in SGA, LGA and GD cases were less prominent, the overall profiles of expressional disturbances overlapped among pregnancy complications providing support to shared placental responses. The dataset represent a rich catalogue for potential biomarkers and therapeutic targets.

No MeSH data available.


Related in: MedlinePlus