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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

Examples of technical replicates from the experimental validation of differentially expressed placental genes in pregnancy complications.Plots represent gene expression fold changes relative to the median value of the normal pregnancy samples (treated as the reference level = 1) in the discovery RNA-Seq dataset (pink; n = 8 samples/group), in the validation by Taqman RT-qPCR (green; n = 8 samples/group) and in the complete Taqman RT-qPCR dataset (blue; n = 24 samples/group). (a) Genes with the highest statistical significance in gene expression shift in pre-eclamptic (PE) placentas (RT-qPCR: FDR <0.05; Supplementary Table S3) show concordant effect directions in the PE and small-for-gestational-age (SGA) groups. (b) Placental expression of SLC16A3 in gestational diabetes (GD) and large for gestational age (LGA) groups. (c) LEP and TET3 show elevated transcript level in PE and SGA placentas compared to other pregnancy outcomes. Asterisks (*) indicate differential expression meeting the statistical significance criteria either for the RNA-Seq (DESeq: FDR < 0.1, DESeq2: FDR < 0.05) or RT-qPCR (FDR < 0.05) datasets. CDR2L, cerebellar degeneration-related protein 2-like; DOT1L, DOT1-like histone H3K79 methyltransferase; FLT1, fms-related tyrosine kinase 1; GRAMD1A, GRAM domain containing 1A; HSD17B1, hydroxysteroid (17-beta) dehydrogenase 1; IGHA1, immunoglobulin heavy constant alpha 1; LEP, leptin; MC1R, melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor); TET3, tet methylcytosine dioxygenase 3; TMEM74B, transmembrane protein 74B; SLC16A3, solute carrier family 16 (monocarboxylate transporter); STX1B, syntaxin 1B.
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f4: Examples of technical replicates from the experimental validation of differentially expressed placental genes in pregnancy complications.Plots represent gene expression fold changes relative to the median value of the normal pregnancy samples (treated as the reference level = 1) in the discovery RNA-Seq dataset (pink; n = 8 samples/group), in the validation by Taqman RT-qPCR (green; n = 8 samples/group) and in the complete Taqman RT-qPCR dataset (blue; n = 24 samples/group). (a) Genes with the highest statistical significance in gene expression shift in pre-eclamptic (PE) placentas (RT-qPCR: FDR <0.05; Supplementary Table S3) show concordant effect directions in the PE and small-for-gestational-age (SGA) groups. (b) Placental expression of SLC16A3 in gestational diabetes (GD) and large for gestational age (LGA) groups. (c) LEP and TET3 show elevated transcript level in PE and SGA placentas compared to other pregnancy outcomes. Asterisks (*) indicate differential expression meeting the statistical significance criteria either for the RNA-Seq (DESeq: FDR < 0.1, DESeq2: FDR < 0.05) or RT-qPCR (FDR < 0.05) datasets. CDR2L, cerebellar degeneration-related protein 2-like; DOT1L, DOT1-like histone H3K79 methyltransferase; FLT1, fms-related tyrosine kinase 1; GRAMD1A, GRAM domain containing 1A; HSD17B1, hydroxysteroid (17-beta) dehydrogenase 1; IGHA1, immunoglobulin heavy constant alpha 1; LEP, leptin; MC1R, melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor); TET3, tet methylcytosine dioxygenase 3; TMEM74B, transmembrane protein 74B; SLC16A3, solute carrier family 16 (monocarboxylate transporter); STX1B, syntaxin 1B.

Mentions: As PE and SGA placentas have been suggested to share common pathophysiology15, we performed RT-qPCR for the 45 PE-related genes also in the SGA samples (extended sample, SGA, n = 24 vs NORM, n = 24; Table 1). For 78% of genes (n = 35), the direction of expression alteration was concordant between the PE and SGA placentas (Supplementary Table S3). Although for the majority of genes the PE placentas exhibited more prominent change in transcript levels, the effects in the PE and SGA groups were highly correlated (R2 =0.68, linear regression P = 3.80 × 10−12; Fig. 3d). The top-loci TMEM74B, FLT1, CDR2L showed significant differential expression in both, PE and SGA placentas (FDR < 0.05; Fig. 4a).


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)

Examples of technical replicates from the experimental validation of differentially expressed placental genes in pregnancy complications.Plots represent gene expression fold changes relative to the median value of the normal pregnancy samples (treated as the reference level = 1) in the discovery RNA-Seq dataset (pink; n = 8 samples/group), in the validation by Taqman RT-qPCR (green; n = 8 samples/group) and in the complete Taqman RT-qPCR dataset (blue; n = 24 samples/group). (a) Genes with the highest statistical significance in gene expression shift in pre-eclamptic (PE) placentas (RT-qPCR: FDR <0.05; Supplementary Table S3) show concordant effect directions in the PE and small-for-gestational-age (SGA) groups. (b) Placental expression of SLC16A3 in gestational diabetes (GD) and large for gestational age (LGA) groups. (c) LEP and TET3 show elevated transcript level in PE and SGA placentas compared to other pregnancy outcomes. Asterisks (*) indicate differential expression meeting the statistical significance criteria either for the RNA-Seq (DESeq: FDR < 0.1, DESeq2: FDR < 0.05) or RT-qPCR (FDR < 0.05) datasets. CDR2L, cerebellar degeneration-related protein 2-like; DOT1L, DOT1-like histone H3K79 methyltransferase; FLT1, fms-related tyrosine kinase 1; GRAMD1A, GRAM domain containing 1A; HSD17B1, hydroxysteroid (17-beta) dehydrogenase 1; IGHA1, immunoglobulin heavy constant alpha 1; LEP, leptin; MC1R, melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor); TET3, tet methylcytosine dioxygenase 3; TMEM74B, transmembrane protein 74B; SLC16A3, solute carrier family 16 (monocarboxylate transporter); STX1B, syntaxin 1B.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Examples of technical replicates from the experimental validation of differentially expressed placental genes in pregnancy complications.Plots represent gene expression fold changes relative to the median value of the normal pregnancy samples (treated as the reference level = 1) in the discovery RNA-Seq dataset (pink; n = 8 samples/group), in the validation by Taqman RT-qPCR (green; n = 8 samples/group) and in the complete Taqman RT-qPCR dataset (blue; n = 24 samples/group). (a) Genes with the highest statistical significance in gene expression shift in pre-eclamptic (PE) placentas (RT-qPCR: FDR <0.05; Supplementary Table S3) show concordant effect directions in the PE and small-for-gestational-age (SGA) groups. (b) Placental expression of SLC16A3 in gestational diabetes (GD) and large for gestational age (LGA) groups. (c) LEP and TET3 show elevated transcript level in PE and SGA placentas compared to other pregnancy outcomes. Asterisks (*) indicate differential expression meeting the statistical significance criteria either for the RNA-Seq (DESeq: FDR < 0.1, DESeq2: FDR < 0.05) or RT-qPCR (FDR < 0.05) datasets. CDR2L, cerebellar degeneration-related protein 2-like; DOT1L, DOT1-like histone H3K79 methyltransferase; FLT1, fms-related tyrosine kinase 1; GRAMD1A, GRAM domain containing 1A; HSD17B1, hydroxysteroid (17-beta) dehydrogenase 1; IGHA1, immunoglobulin heavy constant alpha 1; LEP, leptin; MC1R, melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor); TET3, tet methylcytosine dioxygenase 3; TMEM74B, transmembrane protein 74B; SLC16A3, solute carrier family 16 (monocarboxylate transporter); STX1B, syntaxin 1B.
Mentions: As PE and SGA placentas have been suggested to share common pathophysiology15, we performed RT-qPCR for the 45 PE-related genes also in the SGA samples (extended sample, SGA, n = 24 vs NORM, n = 24; Table 1). For 78% of genes (n = 35), the direction of expression alteration was concordant between the PE and SGA placentas (Supplementary Table S3). Although for the majority of genes the PE placentas exhibited more prominent change in transcript levels, the effects in the PE and SGA groups were highly correlated (R2 =0.68, linear regression P = 3.80 × 10−12; Fig. 3d). The top-loci TMEM74B, FLT1, CDR2L showed significant differential expression in both, PE and SGA placentas (FDR < 0.05; Fig. 4a).

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