Widespread domain-like perturbations of DNA methylation in whole blood of Down syndrome neonates
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PROVIDER: PRJNA419323 | ENA |
REPOSITORIES: ENA
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Project description:IntroductionDown syndrome (DS) is the most frequent genetic cause of intellectual disability. Despite the fact that more than 50 years have passed since the discovery of its genetic aberrations, the exact pathogenesis of the DS phenotype has remained largely unexplained. It was recently hypothesized that the DS pathogenesis involves complex (epi)genetic, molecular and cellular determinants. To date, many reports have addressed epigenetic aberrations associated with DS at different developmental stages/ages and tissue types, but to our best knowledge not in DS newborns. This study aimed to investigate genome-wide methylation patterns in DS newborns compared to non-trisomic newborns.MethodWe analyzed blood samples obtained from ten newborns with DS and five age-matched non-trisomic newborns. Epigenetic profiles were obtained from extracted DNA using the Illumina Infinium 450K array. Since aberrant blood cell distribution is known to be present in DS, we applied two distinct models: with and without correction for estimated blood cell distribution.ResultsDifferentially methylated position (DMP) analysis of the uncorrected model detected 19525 significant hits (51,2% hypomethylated). In the corrected model, we found 121953 significant DMPs (49,8% hypomethylated). Independent of the used model we observed a chromosome 21 dosage effect. Moreover, we detected 46 and 145 differentially methylated regions in the uncorrected and corrected model respectively, both showing hypomethylation overrepresentation. Replication analyses of DMPs and DMRs found by Bacalini et al. (2015) showed a large overlap.ConclusionIn this study, we found methylation profile differences between DS newborns and controls reflecting a systematically affected epigenetic profile. The observed chromosome 21 dosage effect suggests the involvement of affected essential regulatory factors/regions or altered expression of chromatin modeling enzymes located on chromosome 21. Additional research is necessary to substantiate these hypotheses.
| S-EPMC5877863 | biostudies-literature
Project description:Epigenetic (N=15) were based on the Illumina Infinium HumanMethylation450 BeadChip. We searched for differentially methylated probes (DMPs) and regions (DMRs).
2018-03-19 | GSE107211 | GEO
Project description:Disruptions in core cellular processes elicit stress responses that drive cell state changes leading to organismal phenotypes. Perturbations in the splicing machinery cause widespread mis-splicing, resulting in p53-dependent cell-state changes that give rise to cell-type specific phenotypes and disease. However, a unified framework for how cells respond to splicing perturbations, and how this response manifests itself in nuanced disease phenotypes, has yet to be established. Here, we show that a p53-stabilizing Mdm2 alternative splicing event and widespread downregulation of metabolic transcripts are common events that arise under various splicing perturbations in both cellular and organismal models. Together, our results classify a common cellular response to splicing perturbations, put forth a new mechanism behind the cell-type specific phenotypes that arise when splicing is broadly disrupted, and lend insight into the pleiotropic nature of the effects of p53 stabilization in disease.
2024-02-12 | GSE235172 | GEO
Project description:How disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. The majority of disease-associated alleles exhibit wild-type chaperone binding profiles, suggesting they preserve protein folding or stability. While common variants from healthy individuals rarely affect interactions, two-thirds of disease-associated alleles perturb protein-protein interactions, with half corresponding to "edgetic" alleles affecting only a subset of interactions while leaving most other interactions unperturbed. With transcription factors, many alleles that leave protein-protein interactions intact affect DNA binding. Different mutations in the same gene leading to different interaction profiles often result in distinct disease phenotypes. Thus disease-associated alleles that perturb distinct protein activities rather than grossly affecting folding and stability are relatively widespread.
| S-EPMC4441215 | biostudies-other
Project description:The first wave of Foxp3+ regulatory T cells (Tregs) generated in neonates has been reported to be indispensable for the life-long prevention of autoimmunity. Although it is widely accepted that neonates are highly susceptible to infections, the impact of neonatal infections on the first wave of Tregs is completely unknown. Here, we challenged newborn Treg fate-mapping mice (Foxp3eGFPCreERT2xRosa26-YFP) with the Toll-like receptor agonists LPS and poly I:C to mimic neonatal bacterial or viral infections, respectively, and subsequently administrated tamoxifen during the first eight days of life to selectively label the first wave of Tregs. Neonatally-tagged Tregs preferentially accumulated in non-lymphoid tissues when compared to lymphoid organs irrespective of the treatment. One week post perturbation, unexpectedly no differences in the frequency and phenotypes of neonatally-tagged Tregs were observed between challenged mice and untreated controls. However, upon aging, a decreased frequency of neonatally-tagged Tregs in both non-lymphoid tissues and lymphoid organs was detected in challenged mice when compared to untreated controls, and became significant twelve weeks post perturbation, with no signs of altered Foxp3 stability. Remarkably, this late decrease in the frequency of neonatally-tagged Tregs only occurred upon perturbations in newborns as challenging of eight-day-old mice did not result in long-lasting alterations of the first wave of Tregs. Combined single-cell T cell receptor (TCR)-seq and RNA-seq revealed that neonatal perturbations drastically diminished TCR diversity and long-lastingly altered the transcriptome of neonatally tagged Tregs, exemplified by lower expression of Tigit, Foxp3, and Il2ra. Together, our data demonstrate that a single, transient encounter with a pathogen in neonates can have long-lasting consequences for the first wave of Tregs, which might affect immunological tolerance, prevention of autoimmunity, and other non-canonical functions of tissue-resident Tregs.
2022-08-23 | GSE205466 | GEO
Project description:Misidentification of Klebsiella variicola isolated from neonates in two German hospitals
| PRJEB25904 | ENA
Project description:Genome wide DNA methylation profiling of human cord blood mononuclear leokocytes (CBML) from neonates exposed to histological chorioamnionitis (HCA) compared to healthy neonates. The Infinium HumanMethylationEPIC BeadChip array was used to obtain DNA methylation profiles across 866,836 CpGs in five HCA and five control samples.
2020-07-31 | GSE153668 | GEO
Project description:It has been proposed that developmental differences exist between neonatal and adult platelets. Detailed insight therein is, however, still lacking. We have now compared the platelet protein expression profile of neonates and adults employing a label-free quantitative mass spectrometry approach. In addition, platelet aggregation mediated by thromboxane A2 analog, collagen, and peptide agonists of the protease-activated-receptors 1 and 4 was assessed. Results showed that neonatal platelets effectively aggregate in the presence the employed platelet agonists. In agreement with previous studies, higher concentrations of the agonists were required to initiate aggregation in the neonatal platelets. Mass spectrometry analysis revealed no significant difference in the expression level of critical adhesive platelet proteins like glycoprotein (GP)Ib, integrin αIIbβ3, GPV and GPIX. Neonatal platelets did show reduced expression levels of proteins involved in intracellular signaling, i.e. LYN, MAP3k5 and FAM129A. Several proteins that are known to be related to mitochondrial energy metabolism processes such as oxidative phosphorylation, i.e. NDUFS3, NDUFS8 and NDUFA1 were upregulated in neonates. In conclusion, this study reveals that the platelets derived from neonates and adults are distinct. In particular, developmental changes were observed for proteins that belong to metabolic and energy generation processes.
2021-02-05 | PXD004578 | Pride
Project description:Human transcriptome array analysis of human cord blood mononuclear leokocytes from neonates exposed to histological chorioamnionitis and compared with healthy neonates Histological chorioamnionitis (HCA) is an infection of fetal membranes and complicates 5.2% to 28.5% of all live births. Exposure to HCA may have long-term consequences including an increased risk for allergic disorders and asthma later in childhood, the mechanism(s) of which are still not yet well understood. Our objective was to determine the mRNA transcriptome of cord blood mononuclear leukocytes from term neonates and identify key genes and pathways involved in HCA. We found several key genes differentially expressed with exposure to HCA. These transcriptomes included novel genes and pathways associated with exposure to HCA. The differential gene expression included the key genes regulating inflammatory, immune, respiratory and neurological pathways, which may contribute to disorders in those pathways in neonates exposed to HCA.
2019-04-05 | GSE120855 | GEO