Dataset Information

The Cellular Transcriptome in the Maternal Circulation During Normal Pregnancy: A Longitudinal Study.

ABSTRACT: Pregnancy represents a unique immunological state in which the mother adapts to tolerate the semi-allogenic conceptus; yet, the cellular dynamics in the maternal circulation are poorly understood. Using exon-level expression profiling of up to six longitudinal whole blood samples from 49 pregnant women, we undertook a systems biology analysis of the cellular transcriptome dynamics and its correlation with the plasma proteome. We found that: (1) chromosome 14 was the most enriched in transcripts differentially expressed throughout normal pregnancy; (2) the strongest expression changes followed three distinct longitudinal patterns, with genes related to host immune response (e.g., MMP8, DEFA1B, DEFA4, and LTF) showing a steady increase in expression from 10 to 40 weeks of gestation; (3) multiple biological processes and pathways related to immunity and inflammation were modulated during gestation; (4) genes changing with gestation were among those specific to T cells, B cells, CD71+ erythroid cells, natural killer cells, and endothelial cells, as defined based on the GNF Gene Expression Atlas; (5) the average expression of mRNA signatures of T cells, B cells, and erythroid cells followed unique patterns during gestation; (6) the correlation between mRNA and protein abundance was higher for mRNAs that were differentially expressed throughout gestation than for those that were not, and significant mRNA-protein correlations were observed for genes part of the T-cell signature. In summary, unique changes in immune-related genes were discovered by longitudinally assessing the cellular transcriptome in the maternal circulation throughout normal pregnancy, and positive correlations were noted between the cellular transcriptome and plasma proteome for specific genes/proteins. These findings provide insights into the immunobiology of normal pregnancy.

SUBMITTER: Gomez-Lopez N

PROVIDER: S-EPMC6928201 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Cellular Transcriptome in the Maternal Circulation During Normal Pregnancy: A Longitudinal Study.

Gomez-Lopez Nardhy N Romero Roberto R Hassan Sonia S SS Bhatti Gaurav G Berry Stanley M SM Kusanovic Juan Pedro JP Pacora Percy P Tarca Adi L AL

Frontiers in immunology 20191217

Pregnancy represents a unique immunological state in which the mother adapts to tolerate the semi-allogenic conceptus; yet, the cellular dynamics in the maternal circulation are poorly understood. Using exon-level expression profiling of up to six longitudinal whole blood samples from 49 pregnant women, we undertook a systems biology analysis of the cellular transcriptome dynamics and its correlation with the plasma proteome. We found that: (1) chromosome 14 was the most enriched in transcripts ...[more]

PMID: 31921132

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Project description:BackgroundThe amniotic fluid (AF) cell-free transcriptome is modulated by physiologic and pathologic processes during pregnancy. AF gene expression changes with advancing gestation reflect fetal development and organ maturation; yet, defining normal expression and splicing patterns for biomarker discovery in obstetrics requires larger heterogeneous cohorts, evaluation of potential confounding factors, and novel analytical approaches.MethodsWomen with a normal pregnancy who had an AF sample collected during midtrimester (n?=?30) or at term gestation (n?=?68) were included. Expression profiling at exon level resolution was performed using Human Transcriptome Arrays. Differential expression was based on moderated t-test adjusted p?<?0.05 and fold change >?1.25; for differential splicing, a splicing index >?2 and adjusted p?<?0.05 were required. Functional profiling was used to interpret differentially expressed or spliced genes. The expression of tissue-specific and cell-type specific signatures defined by single-cell genomics was quantified and correlated with covariates. In-silico validation studies were performed using publicly available datasets.Results1) 64,071 genes were detected in AF, with 11% of the coding and 6% of the non-coding genes being differentially expressed between midtrimester and term gestation. Expression changes were highly correlated with those previously reported (R?>?0.79, p?<?0.001) and featured increased expression of genes specific to the trachea, salivary glands, and lung and decreased expression of genes specific to the cardiac myocytes, uterus, and fetal liver, among others. 2) Single-cell RNA-seq signatures of the cytotrophoblast, Hofbauer cells, erythrocytes, monocytes, T and B cells, among others, showed complex patterns of modulation with gestation (adjusted p?<?0.05). 3) In 17% of the genes detected, we found differential splicing with advancing gestation in genes related to brain development processes and immunity pathways, including some that were missed based on differential expression analysis alone.ConclusionsThis represents the largest AF transcriptomics study in normal pregnancy, reporting for the first time that single-cell genomic signatures can be tracked in the AF and display complex patterns of expression during gestation. We also demonstrate a role for alternative splicing in tissue-identity acquisition, organ development, and immune processes. The results herein may have implications for the development of fetal testing to assess placental function and fetal organ maturity.

Project description:ObjectivePregnancy is accompanied by dramatic physiological changes in maternal plasma proteins. Characterization of the maternal plasma proteome in normal pregnancy is an essential step for understanding changes to predict pregnancy outcome. The objective of this study was to describe maternal plasma proteins that change in abundance with advancing gestational age and determine biological processes that are perturbed in normal pregnancy.Study designA longitudinal study included 43 normal pregnancies that had a term delivery of an infant who was appropriate for gestational age without maternal or neonatal complications. For each pregnancy, 3 to 6 maternal plasma samples (median, 5) were profiled to measure the abundance of 1125 proteins using multiplex assays. Linear mixed-effects models with polynomial splines were used to model protein abundance as a function of gestational age, and the significance of the association was inferred via likelihood ratio tests. Proteins considered to be significantly changed were defined as having the following: (1) >1.5-fold change between 8 and 40 weeks of gestation; and (2) a false discovery rate-adjusted value of P < .1. Gene ontology enrichment analysis was used to identify biological processes overrepresented among the proteins that changed with advancing gestation.ResultsThe following results were found: (1) Ten percent (112 of 1125) of the profiled proteins changed in abundance as a function of gestational age; (2) of the 1125 proteins analyzed, glypican-3, sialic acid-binding immunoglobulin-type lectin-6, placental growth factor, C-C motif-28, carbonic anhydrase 6, prolactin, interleukin-1 receptor 4, dual-specificity mitogen-activated protein kinase 4, and pregnancy-associated plasma protein-A had more than a 5-fold change in abundance across gestation (these 9 proteins are known to be involved in a wide range of both physiological and pathological processes, such as growth regulation, embryogenesis, angiogenesis immunoregulation, inflammation etc); and (3) biological processes associated with protein changes in normal pregnancy included defense response, defense response to bacteria, proteolysis, and leukocyte migration (false discovery rate, 10%).ConclusionThe plasma proteome of normal pregnancy demonstrates dramatic changes in both the magnitude of changes and the fraction of the proteins involved. Such information is important to understand the physiology of pregnancy and the development of biomarkers to differentiate normal vs abnormal pregnancy and determine the response to interventions.

Project description:In the post-genomic era, our understanding of the molecular regulators of physiologic and pathologic processes in pregnancy is expanding at the whole-genome level. Longitudinal changes in the known protein-coding transcriptome during normal pregnancy, which we recently reported (Gomez-Lopez et al., 2019), have improved our definition of the major operant networks, yet pregnancy-related functions of the non-coding RNA transcriptome remain poorly understood. A key finding of the ENCODE (Encyclopedia of DNA Elements) Consortium, the successor of the Human Genome Project, was that the human genome contains approximately 60,000 genes, the majority of which do not encode proteins. The total transcriptional output of non-protein-coding RNA genes, collectively referred to as the non-coding transcriptome, is comprised mainly of long non-coding RNA (lncRNA) transcripts (Derrien et al., 2012). Although the ncRNA transcriptome eclipses its protein-coding counterpart in abundance, it has until recently lacked a comprehensive, unbiased, genome-scale characterization over the timecourse of normal human pregnancy. Here, we annotated, characterized, and selectively validated the longitudinal changes in the non-coding transcriptome of maternal whole blood during normal pregnancy to term. We identified nine long non-coding RNAs (lncRNAs), including long intergenic non-coding RNAs (lincRNAs) as well as lncRNAs antisense to or otherwise in the immediate vicinity of protein-coding genes, that were differentially expressed with advancing gestation in normal pregnancy: AL355711, BC039551 (expressed mainly in the placenta), JHDM1D-AS1, A2M-AS1, MANEA-AS1, NR_034004, LINC00649, LINC00861, and LINC01094. By cross-referencing our dataset against major public pseudogene catalogs, we also identified six transcribed pseudogenes that were differentially expressed over time during normal pregnancy in maternal blood: UBBP4, FOXO3B, two Makorin (MKRN) pseudogenes (MKRN9P and LOC441455), PSME2P2, and YBX3P1. We also identified three non-coding RNAs belonging to other classes that were modulated during gestation: the microRNA MIR4439, the small nucleolar RNA (snoRNA) SNORD41, and the small Cajal-body specific ncRNA SCARNA2. The expression profiles of most hits were broadly suggestive of functions in pregnancy. These time-dependent changes of the non-coding transcriptome during normal pregnancy, which may confer specific regulatory impacts on their protein-coding gene targets, will facilitate a deeper molecular understanding of pregnancy and lncRNA-mediated molecular pathways at the maternal-fetal interface and of how these pathways impact maternal and fetal health.

Project description:Background and objectivesThe neurodevelopment of the offspring is suggested to be influenced by the maternal immune system's responses throughout pregnancy, which in turn is also vulnerable to maternal psychosocial stress conditions. Therefore, our main goal was to investigate whether maternal peripheral immunological biomarkers (IB) during two stages of gestation are associated with distinct neurodevelopmental trajectories in the first two years of life. As a second goal, we also explored the association between maternal distal (childhood) and proximal (gestation) stressful experiences and the immunological markers assessed during pregnancy.MethodsMaternal childhood trauma, depressive and anxiety symptoms, and peripheral IB (IFNγ, IL-10, IL1β, IL6, IL8, TNFα, EGF, IL13, IL17, IL1Ra and IL4) were measured at baseline (8-16 weeks of pregnancy) and at 30 weeks of pregnancy in 160 women. The participants had the blood samples collected from two randomized clinical trials conducted by the same team and methods in the same community. A Principal Component Analysis (PCA) was implemented to create meaningful composite variables that describe the cytokines joint variation. Finally, linear mixed-effects modeling was used to investigate the influence of inflammatory biomarkers, maternal childhood trauma, anxiety, and depressive symptoms on Bayley's III scores trajectories.ResultsThe IB profile during the 3rd trimester of pregnancy predicted the offspring's neurodevelopmental trajectories in the first two years of life. The components derived from PCA were important predictors and captured different immune responses, reflecting both pro- and anti-inflammatory states. Maternal stressful experiences did not correlate with the immunological markers. Although not a reliable predictor alone, maternal psychosocial stress at the 1st trimester of pregnancy interacted with the mother's immune response while predicting the neurodevelopmental scores during the first two years of life.ConclusionsOur results underscore the importance of the maternal immune response during pregnancy in shaping the neurodevelopmental trajectory of the offspring. Additionally, we observed that the maternal distress at the early stages of pregnancy has an incremental effect on the neurodevelopmental outcome but depends upon the immune response.

Dataset Information

The Cellular Transcriptome in the Maternal Circulation During Normal Pregnancy: A Longitudinal Study.

Publications

The Cellular Transcriptome in the Maternal Circulation During Normal Pregnancy: A Longitudinal Study.

Similar Datasets

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