Identification of large offspring syndrome during pregnancy through maternal blood transcriptome analyses
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ABSTRACT:
ORGANISM(S): Bos taurus
PROVIDER: GSE179946 | GEO | 2022/06/29
REPOSITORIES: GEO
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Project description:Embryos generated with the use of assisted reproductive technologies (ART) can develop overgrowth syndromes. In ruminants, the condition is referred to as large offspring syndrome (LOS) and exhibits variable phenotypic abnormalities including overgrowth, enlarged tongue, and abdominal wall defects. These characteristics recapitulate those observed in the human loss-of-imprinting (LOI) overgrowth syndrome Beckwith-Wiedemann (BWS). We have recently shown LOI at the KCNQ1 locus in LOS, the most common epimutation in BWS. Although the first case of ART-induced LOS was reported in 1995, studies have not yet determined the extent of LOI in this condition. Here, we determined allele-specific expression of imprinted genes previously identified in human and/or mouse in day 105 Bos taurus indicus X Bos taurus taurus F1 hybrid control and LOS fetuses using RNAseq. Our analysis allowed us to determine the monoallelic expression of 20 genes in tissues of control fetuses. LOS fetuses displayed variable LOI when compared to controls. Biallelic expression of imprinted genes in LOS was associated with tissue-specific hypomethylation of the normally methylated parental allele. In addition, a positive correlation was observed between bodyweight and the number of biallelically expressed imprinted genes in LOS fetuses. Further, not only was there loss of allele-specific expression of imprinted genes in LOS, but we also observed differential transcript amounts of these genes between control and overgrown fetuses. In summary, we characterized previously unidentified imprinted genes in bovine and identified misregulation of imprinting at multiple loci in LOS. We concluded that LOS is a multi-locus loss-of-imprinting syndrome, as is BWS.
2015-03-06 | GSE63509 | GEO
Project description:Assisted reproductive therapies (ART) have become increasingly common worldwide and up to ~6% of children currently born in developed countries were conceived employing these technologies. Numerous retrospective studies have suggested that ART-conceived children are more likely to develop the overgrowth syndrome Beckwith-Wiedemann (BWS). In bovine, the use of ART can induce a similar overgrown condition, which is referred to as large offspring syndrome (LOS). Both BWS and LOS involve dysregulation of imprinted genes. However, it remains largely unknown whether aberrant gene expression and DNA methylation occur at non-imprinted loci and to what extent these molecular alterations can contribute to these syndromes. Here we examined the transcriptome of skeletal muscle, liver, kidney, and brain of control and LOS bovine fetuses and found that different LOS fetuses exhibit different severity of the transcriptome alterations and different tissues have distinct gene pathways disturbed in LOS fetuses. Particularly for skeletal muscle, multiple pathways involved in myoblast proliferation and fusion into myotubes are misregulated in LOS fetuses. Further, characterization of the methylome of skeletal muscle demonstrates numerous local methylation differences; however, global DNA methylation is comparable between all individuals regardless of bodyweight. Importantly, only a small percent of differentially expressed genes (DEGs) including the imprinted gene IGF2R can be linked to the neighboring differentially methylated regions (DMRs). In summary, we not only show that misregulation of non-imprinted genes in addition to loss-of-imprinting contributes to the ART-induced overgrowth syndrome but also demonstrate that most of the aberrant gene expression is not associated with DNA methylome epimutations.
2017-10-31 | GSE93775 | GEO
Project description:Poor maternal nutrition causes intrauterine growth restriction (IUGR); however, its effects on fetal cardiac development are unclear. We have developed a baboon model of moderate maternal undernutrition, leading to IUGR. We hypothesized that the IUGR affects fetal cardiac structure and metabolism. Six control pregnant baboons ate ad-libitum (CTRL)) or 70% CTRL from 0.16 of gestation (G). Fetuses were euthanized at C-section at 0.9G under general anesthesia. Male but not female IUGR fetuses showed left ventricular fibrosis inversely correlated with birth weight. Expression of extracellular matrix protein TSP-1 was increased (p<0.05) in male IUGR. Expression of cardiac fibrotic markers TGFß, SMAD3 and ALK-1 were downregulated in male IUGRs with no difference in females. Autophagy was present in male IUGR evidenced by upregulation of ATG7 expression and lipidation LC3B. Global miRNA expression profiling revealed 56 annotated and novel cardiac miRNAs exclusively dysregulated in female IUGR, and 38 cardiac miRNAs were exclusively dysregulated in males (p<0.05). Fifteen (CTRL) and 23 (IUGR) miRNAs, were differentially expressed between males and females (p<0.05) suggesting sexual dimorphism, which can be at least partially explained by differential expression of upstream transcription factors (e.g. HNF4a, and NF?B p50). Lipidomics analysis of fetal cardiac tissue exhibited a net increase in diacylglycerol and plasmalogens and a decrease in triglycerides and phosphatidylcholines. In summary, IUGR resulting from decreased maternal nutrition is associated with sex-dependent dysregulations in cardiac structure, miRNA expression, and lipid metabolism. If these changes persist postnatally, they may program offspring for higher later life cardiac risk.
2018-04-30 | MTBLS426 | MetaboLights
Project description:The aim of this work was to evaluate the influence of maternal and embryonic genotype of two lines of rabbit selected by growth rate (line R) and litter size at weaning (line A) on foetal and placental growth. Embryos were recovered at 48 h of gestation from line R (46) and line A (40) donors and transferred to nulliparous recipient does (26 R and 24 A). Each recipient doe received six embryos into one oviduct from line R and six embryos form line A into the other. Laparoscopy was performed at day 14 to determine implantation rate. Recipient females were slaughter at day 14, 24 and 30 (12, 24, 14, respectively) to determine the number of live fetuses and the weight of live foetuses, foetal placenta and maternal placenta. To analyze endocrine levels, blood serum was collected from 14 females at 14, 21 and 28 days of gestation. A transcriptome analysis was performed to search for differences between foetal placentas at day 14 and 24 of development. Foetal survival at Days 14, 24 and 30, and weight at Day 14 was higher for line A embryos, being the weight higher for AA genotype (0.29±0.01g vs. 0.19±0.01g ,for RR genotype). Only the R embryonic genotype showed higher foetal weight at Day 30 (53.4 ± 1.74 vs. 48.5 ± 1.81, for line R and line A foetuses). However, foetal and maternal placentas were higher for RR genotype on Day 24 and 30. No differences in foetal placenta at transcriptome level were found. Additionally, both progesterone and IGF-I levels were similar between lines. In conclusion, line R presented reproductive troubles, with higher gestational losses at embryonary level at Day 14 and 24, and uterine environment problems at least at last part of gestation which reduced survival rate of A line foetuses. Embryos were recovered at 48 h of gestation from line R and line A donors and transferred to nulliparous recipient does. Recipient females were slaughter at Day 14 and 24, and a transcriptomic comparison analysis was performed from foetal placenta tissue.
2014-10-21 | E-GEOD-62491 | biostudies-arrayexpress
Project description:Host immune responses during late-onset sepsis (LOS) in very preterm infants are poorly characterised due to a complex and dynamic pathophysiology and challenges in working with small available blood volumes. We present here an unbiased transcriptomic analysis of whole peripheral blood from very preterm infants at the time of LOS. RNA-Seq was performed on peripheral blood samples (6 – 29 days postnatal age) taken at the time of suspected LOS from very preterm infants <30 weeks gestational age. Infants were classified based on blood culture positivity and elevated C-reactive protein concentrations as having confirmed LOS (n=5), possible LOS (n=4) or no LOS (n=9). Bioinformatics and statistical analyses performed included pathway over-representation and protein-protein interaction network analyses. Plasma cytokine immunoassays were performed to validate differentially expressed cytokine pathways.The blood leukocyte transcriptional responses of infants with confirmed LOS differed significantly from infants without LOS (1,317 differentially expressed genes). However, infants with possible LOS could not be distinguished from infants with no LOS or confirmed LOS. Transcriptional alterations associated with LOS included genes involved in pathogen recognition (mainly TLR pathways), cytokine signalling (both pro-inflammatory and inhibitory responses), immune and haematological regulation (including cell death pathways), and metabolism (altered cholesterol biosynthesis). At the transcriptional-level cytokine responses during LOS were characterised by over-representation of IFN-α/β, IFN-γ, IL-1 and IL-6 signalling pathways and up-regulation of genes for inflammatory responses. Infants with confirmed LOS had significantly higher levels of IL-1α and IL-6 in their plasma. Blood responses in very preterm infants with LOS are characterised by altered host immune responses that appear to reflect unbalanced immuno-metabolic homeostasis.
2020-06-03 | GSE138712 | GEO
Project description:Intra-uterine growth restriction (IUGR) and fetal overgrowth increase the risk of postnatal health. Maternal nutrition is the major intrauterine environmental factor that alters fetal weight. However, the mechanisms underlying maternal nutrition affect fetal development is not entirely clear. We developed a pig model and used isobaric tags for relative and absolute quantification (iTRAQ) to investigate alterations in the placental proteome were obtained from gilts in normal-energy-intake (Con) and high-energy-intake (HE) group, respectively.At 90 d of gestation, the heavy fetuses were found at the tubal ends and light fetuses at the cervical ends of the uterus in Con group and the heavy fetuses had higher glucose concentration than the light fetuses. However, a higher uniformity was noted in HE group. Placental promote between these two positions indicated that a total of 78 and 50 differentially expressed proteins were detected in Con and HE group, respectively. In Con group, these proteins related to lipid metabolism (HADHA, AACS, CAD), nutrient transport (GLUT, SLC27A1) and energy metabolism (NDUFV1, NDUFV2, ATP5C1). However, the differentially expressed proteins in HE group were mainly participation in transcriptional and translational regulation and intracellular vesicular transport.
2018-10-26 | PXD004951 | Pride
Project description:Background: Congenital cytomegalovirus (cCMV) is a common intrauterine infection, leading to neurodevelopmental disabilities. Early prognostic assessment of the severity of cCMV has remained an ongoing challenge. We aimed to identify amniotic fluid biomarkers of the severity of cCMV-related fetal brain injury. Methods: Global proteome analysis was performed in mid-gestation amniotic fluid samples, comparing fetuses with severe cCMV to asymptomatic CMV-infected fetuses (the discovery cohort). The levels of selected differentially-excreted proteins were further determined by specific immunoassays, and evaluated in an independent validation cohort, including clinically-blinded amniotic fluid of CMV-infected fetuses from unrelated centers. Findings: Proteome analysis identified 29 amniotic fluid proteins with distinct abundance in fetuses with severe-, compared to asymptomatic, cCMV. Pathway analysis of the differentially-excreted proteins revealed enriched pathways of inflammatory response, cellular compromise, immunological disease, organismal injury, and neurological disease, underlining a link between excessive inflammation at the maternal-fetal interface and the development of cCMV-related fetal brain damage. Importantly, the levels of two of these proteins, chemerin and galectin-3-binding protein (Gal-3BP), selected for validation, demonstrated 88.2% sensitivity (each), 100-96.2% specificity, 100-93.8% positive predictive value, and 92.9-92.6% negative predictive value, with 0.98-0.97 area under the curve (for chemerin - Gal-3BP, respectively) in differentiating 17 fetuses with severe cCMV from 26 asymptomatic CMV-infected fetuses. Interpretation: These results identify the immunomodulatory proteins chemerin and Gal-3BP as new highly predictive amniotic fluid biomarkers of cCMV severity, which could guide early prognostic stratification and potential personalized treatment of cCMV-infected fetuses. Funding: Israel Science Foundation; Research Fund of the Hadassah Medical Organization
2022-05-25 | PXD029105 | Pride
Project description:Background: As couples struggle with infertility and livestock producers wish to rapidly improve genetic merit in their herd, assisted reproductive technologies (ART) have become increasingly popular in human medicine as well as the livestock industry. Utilizing ART can cause an increased risk of congenital overgrowth syndromes, such as Large Offspring Syndrome (LOS) in ruminants. A dysregulation of transcripts has been observed in bovine fetuses with LOS, which is suggested to be a cause of the phenotype. Our recent study identified variations in tRNA expression in LOS individuals, leading us to hypothesize that variations in tRNA expression can influence the availability of their processed regulatory products, tRNA-derived fragments (tRFs). Due to their resemblance in size to microRNAs, studies suggest that tRFs target mRNA transcripts and regulate gene expression. Thus, we have sequenced small RNA isolated from skeletal muscle and liver of day 105 bovine fetuses to elucidate the mechanisms contributing to LOS. Moreover, we have utilized our previously generated tRNA sequencing data to analyze the contribution of tRNA availability to tRF abundance. Results: 22,289 and 7,737 unique tRFs were predicted in the liver and muscle tissue respectively. The greatest number of reads originated from 5′ tRFs in muscle and 5′ halves in liver. In addition, mitochondrial (MT) and nuclear derived tRF expression was tissue-specific with most MT-tRFs and nuclear tRFs derived from LysUUU and iMetCAU in muscle, and AsnGUU and GlyGCC in liver. Despite variation in tRF abundance within treatment groups, we identified differentially expressed (DE) tRFs across Control-AI, ART-Normal, and ART-LOS groups with the most DE tRFs between ART-Normal and ART-LOS groups. Many DE tRFs target transcripts enriched in pathways related to growth and development in the muscle and tumor development in the liver. Finally, we found positive correlation coefficients between tRNA availability and tRF expression in muscle (R = 0.47) and liver (0.6). Conclusion: Our results highlight the dysregulation of tRF expression and its regulatory roles in LOS. These tRFs were found to target both imprinted and non-imprinted genes in muscle as well as genes linked to tumor development in the liver. Furthermore, we found that tRNA transcription is a highly modulated event that plays a part in the biogenesis of tRFs. This study is the first to investigate the relationship between tRNA and tRF expression in combination with ART-induced LOS.
2022-11-15 | GSE213525 | GEO
Project description:The aim of this work was to evaluate the influence of maternal and embryonic genotype of two lines of rabbit selected by growth rate (line R) and litter size at weaning (line A) on foetal and placental growth. Embryos were recovered at 48 h of gestation from line R (46) and line A (40) donors and transferred to nulliparous recipient does (26 R and 24 A). Each recipient doe received six embryos into one oviduct from line R and six embryos form line A into the other. Laparoscopy was performed at day 14 to determine implantation rate. Recipient females were slaughter at day 14, 24 and 30 (12, 24, 14, respectively) to determine the number of live fetuses and the weight of live foetuses, foetal placenta and maternal placenta. To analyze endocrine levels, blood serum was collected from 14 females at 14, 21 and 28 days of gestation. A transcriptome analysis was performed to search for differences between foetal placentas at day 14 and 24 of development. Foetal survival at Days 14, 24 and 30, and weight at Day 14 was higher for line A embryos, being the weight higher for AA genotype (0.29±0.01g vs. 0.19±0.01g ,for RR genotype). Only the R embryonic genotype showed higher foetal weight at Day 30 (53.4 ± 1.74 vs. 48.5 ± 1.81, for line R and line A foetuses). However, foetal and maternal placentas were higher for RR genotype on Day 24 and 30. No differences in foetal placenta at transcriptome level were found. Additionally, both progesterone and IGF-I levels were similar between lines. In conclusion, line R presented reproductive troubles, with higher gestational losses at embryonary level at Day 14 and 24, and uterine environment problems at least at last part of gestation which reduced survival rate of A line foetuses.
2014-10-21 | GSE62491 | GEO
Project description:We have developed a baboon nonhuman primate (NHP) model of maternal nutrient reduction during fetal development (30% global maternal nutrient reduction, MNR) to evaluate the impact of reduced nutrient availability on primate fetal development. We reported (Antonow-Schlorke et al. PNAS, 2011) that MNR induced major cerebral developmental disturbances at mid gestation (0.5G); however, the impact of MNR at late gestation (0.9G) and the mechanisms mediating these effects have not been determined. We hypothesized that MNR alters developmental trajectories of the fetal prefrontal cortex in the late gestation via miRNA regulation of key transcriptional and translational signaling pathways. Pregnant baboons were fed either ad libitum (control; CON; females n=3; males n=3) or a globally reduced diet (70% of controls; females n=3; males n=3) from 0.16G through 0.9G that produces IUGR (14% reduction in fetal weight). Fetuses were removed by Cesarean section at 0.9G, and prefrontal cortex (PFC) sections collected for analysis. Transcriptome (gene arrays) and small transcriptome (small RNA-Seq) analyses of fetal PFC were performed and gene and miRNA profiles were compared between MNR and CON. We present for the first time transcriptome (GSE42756) and small RNA transcriptome expression profiles of the fetal baboon PFC at 0.9G. Pathway analysis showed that MNR had sex-specific effects on key cellular signaling pathways. We conclude that moderate maternal global nutrient reduction during pregnancy can alter signaling pathways related to nutrient sensing and cell proliferation in the late gestation PFC. In addition, inverse expression of miRNAs known to target genes in these pathways suggests that miRNA mechanisms play a role in these changes.
2018-09-03 | GSE61213 | GEO