Discrete placental gene expression signatures of diabetes during pregnancy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1048494 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27056435_1.fastq.gz | Fastqsanger.gz | |||
| SRR27056435_2.fastq.gz | Fastqsanger.gz | |||
| SRR27056436_1.fastq.gz | Fastqsanger.gz | |||
| SRR27056436_2.fastq.gz | Fastqsanger.gz | |||
| SRR27056437_1.fastq.gz | Fastqsanger.gz |
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Project description:BACKGROUND: Although gestational diabetes affects up to 10% of all pregnancies, there is ambiguity as to whether the disease subtype classifications are biologically significant at the maternal-fetal interface, or more reflective of an extended spectrum of normal pregnancy endocrine physiology. OBJECTIVE: Bulk RNA-sequencing (RNA-seq), single-cell RNA-sequencing (scRNA-seq), and spatial transcriptomics have been integrated to reveal gene signatures of disease in subsets of cells and microenvironments. We aimed to combine these high-resolution technologies with rigorous classification of diabetes subtypes in pregnancy. We hypothesized that differences between pre-existing and gestational diabetes subtypes would be associated with altered gene expression profiles in specific placental cell populations. STUDY DESIGN: In a two-phase case-cohort design, we clinically validated gestational diabetes mellitus type 1 (GDMA1), GDMA2, and type 2 diabetes (T2DM) cases within a cohort of placentae and compared them to healthy controls by bulk RNA-seq (n=54). Quantitative analysis with RT-qPCR of presumptive genes of significant interest were undertaken in an independent and non-overlapping validation cohort of similarly well-characterized cases and controls (n=122). Additional integrated analyses of term placenta single-cell, single-nuclei, and spatial transcriptomics data to determine the cellular subpopulations and niches that aligned with the GDMA1, GDMA2, and T2DM gene expression signatures. RESULTS: Dimension reduction of the bulk RNA-seq data revealed that the most common source of placental gene expression variation was diabetic disease subtype. Relative to controls, we found 2,052 unique significantly differentially expressed transcripts (-2<Log2(fold-change)>2 threshold; q<0.05 Wald Test) among GDMA1 placental specimens, 267 among GDMA2, and 1,520 among T2DM. Several candidate marker genes (CSH1, PER1, PIK3CB, FOXO1, EGFR, IL2RB, SOD3, DOCK5, and SOGA1) were validated in an independent and non-overlapping validation cohort (q<0.05 Tukey). Functional enrichment revealed the pathways and genes most impacted for each diabetes subtype, and degree of proximal similarity to other subclassifications. Surprisingly, GDMA1 and T2DM were more proximal by virtue of increased expression of chromatin remodeling and epigenetic regulation genes, while albumin was the top marker for GDMA2 with increased expression of genes in the wound healing pathway. Assessment of these gene signatures in the single-cell, single-nuclei, and spatial transcriptomics data revealed expression of these genes were highly variable by placental cell and microarchitecture type. For example, at the cellular and spatial (e.g., microarchitectural) levels, distinguishing features were observed in in extravillous trophoblasts (GDMA1) and macrophages (GDMA2). Lastly, we utilized these data to generate machine learning models to predict participants diabetes status and observed greater proximity of placental gene expression among GDMA1 and T2DM participants relative to GDMA2. CONCLUSION: Consistent with their distinct risks of perinatal outcomes, placentae from GDMA1, GDMA2, and T2DM affected pregnancies harbor gene signatures which can be further distinguished by placental microarchitecture and cellular subtypes.
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Project description:The placenta is a potent endocrine organ that secretes hormones with metabolic effects into maternal circulation. On the other hand, the liver, which is the main detoxification organ of the body, plays a key role in regulating maternal glucose and insulin metabolism during pregnancy. Failures in the production of placental hormones and/or the liver to adapt its structure and function to pregnancy can result in metabolic diseases such as gestational diabetes. Previous work has shown that the imprinted Igf2-H19 locus is involved in controlling placental endocrine function in mice. This study used conditional mis-expression of the Igf2-H19 locus to induce placental endocrine malfunction and study its consequences on hepatic gene regulation during pregnancy.
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Project description:We report that the effect of GDM on gene expression differs between feto-placental endothelial cells of male vs female progeny, i.e. after pregnancy with a male or female offspring.
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Project description:The hemochorial placenta provides a critical barrier at the maternal-fetal interface to modulate maternal immune tolerance and enable gas and nutrient exchange between mother and conceptus. Pregnancy outcomes are adversely affected by gestational diabetes mellitus (GDM); however, the effects of GDM on placental formation, and subsequently fetal development, are not fully understood. In this report, streptozotocin was used to induce hyperglycemia in pregnant rats for the purpose of investigating the impact of GDM on placental formation and fetal development. GDM caused placentomegaly and placenta malformation, decreasing placental efficiency and fetal size. Elevated glucose disrupted rat trophoblast stem (TS) cell differentiation in vitro. Evidence of altered trophoblast differentiation was also observed in vivo, as hyperglycemia affected the junctional zone transcriptome and interfered with intrauterine trophoblast invasion and uterine spiral artery remodeling. When exposed to hypoxia, rats with GDM showed decreased proliferation and ectoplacental cone development on gestation day (gd) 9.5 and complete pregnancy loss by gd 13.5. Furthermore, elevated glucose concentrations inhibited TS cell responses to hypoxia in vitro. Overall, these results indicate that alterations in placental development, efficiency, and plasticity could contribute to the suboptimal fetal outcomes in offspring from pregnancies complicated by GDM.
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2015-06-18 | E-GEOD-69941 | biostudies-arrayexpress
Project description:Placental-Liver Crosstalk in the Control of Pregnancy
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Project description:We hypothesized that the trophoblast secretes anti-angiogenic factors, which increase in late pregnancy to limit angiogenesis. Therefore, we determined the paracrine effect of primary human trophoblasts from early versus late pregnancy on the angiogenic potential of isolated feto-placental endothelial cells. We found that the expression and secretion of anti-angiogenic factors differs in early vs late pregnancy, and differentially affects feto-placental angiogenesis.
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Project description:Maternal obesity is becoming a major health consideration for successful pregnancy outcomes. There is growing proof that maternal obesity has a negative influence on placental development and function, thereby adversely influencing offspring programming and health outcomes. However, the molecular mechanisms underlying these processes are so far poorly understood. We set out to analyse term placenta whole transcriptome in obese (n=5) and normoweight women (n=5), using Affymetrix microarray platform compromising of 50,000 probe sets. Our analysis shows that the placental transcriptome differs between normoweight and obese women. Different processes and pathways among placenta from obese women were dysregulated, including inflammation and immune responses, lipid metabolism, cell death and survival and cancer pathways, vasculogenesis and angiogenesis, and glucocorticoid receptor signaling pathway. Together, this global gene expression profiling approach demonstrates and confirms that maternal obesity creates a unique in utero environment that impairs placental transcriptome.
2017-01-07 | E-MTAB-4541 | biostudies-arrayexpress
Project description:Pregnancy 25-hydroxyvitamin D (25(OH)D) concentrations are associated with maternal and fetal health outcomes, but the underlying mechanisms have not been elucidated. Using physiological human placental perfusion approaches and intact villous explants we demonstrate a role for the placenta in regulating the relationships between maternal 25(OH)D concentrations and fetal physiology. Here, we demonstrate active placental uptake of 25(OH)D3 by endocytosis and placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the fetal and maternal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than solely the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer, including transcriptional activation and inflammatory responses. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta; with widespread effects on the placenta itself. These data show complex and synergistic interplay between vitamin D and the placenta, and inform possible interventions to optimise placental function to better support fetal growth and the maternal adaptations to pregnancy.
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