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Genome-Wide Mapping of 5-mC and 5-hmC in severely Preeclamptic Placentas.

ABSTRACT: Preeclampsia (PE) is a major contributor of maternal mortality with uncertain etiology. Recent studies suggested that epigenetic modifications, including DNA methylation, play a vital role in the development of PE. In this study, we have mapped genome-wide distribution of 5-methylcytosin (5-mC) and 5-hydroxymethylcytosine (5-hmC) using MeDIP and (h)MeDIP in the placentas from severely preeclamptic patients and normal controls. A total 194485 pooled 5-mC peaks and 138133 pooled 5-hmC peaks were identified, of which 714 5-mC peaks and 119 5-hmC peaks showed significant difference between patients and controls (>2-fold, p<0.05).To our knowledge, this is the first report of DHMRs (Differentially Hydroxy-Methylated Regions) in preeclamptic placenta. We not only confirmed the aberrant DNA methylated regions in the process of preeclampsia reported previously, but also identified unreported regions. A total of 4 selected DMRs (Differentially Methylated Regions) were also confirmed by MassARRAY EppiTYPER. Of these, PTPRN2, which had low level of 5-mC and high level of 5-hmC at gene body, was further verified to have lower methylation level at promoter regions in case group compared with controls. In conclusion, our study provided genome-wide distribution of 5-mC and 5-hmC in severe PE and normal controls, which have further clinical value for the identification of diagnostic and therapeutic markers for severe PE. Examination of 5-mC and 5-hmC pattern in 4 control cases' tissue and 4 severely Preeclamptic Placentas cases' tissue.

ORGANISM(S): Homo sapiens

SUBMITTER: Shi Yang

PROVIDER: E-GEOD-63743 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Genome-Wide Mapping of 5-mC and 5-hmC in severely Preeclamptic Placentas.

Project description:Preeclampsia (PE) is a major contributor of maternal mortality with uncertain etiology. Recent studies suggested that epigenetic modifications, including DNA methylation, play a vital role in the development of PE. In this study, we have mapped genome-wide distribution of 5-methylcytosin (5-mC) and 5-hydroxymethylcytosine (5-hmC) using MeDIP and (h)MeDIP in the placentas from severely preeclamptic patients and normal controls. A total 194485 pooled 5-mC peaks and 138133 pooled 5-hmC peaks were identified, of which 714 5-mC peaks and 119 5-hmC peaks showed significant difference between patients and controls (>2-fold, p<0.05).To our knowledge, this is the first report of DHMRs (Differentially Hydroxy-Methylated Regions) in preeclamptic placenta. We not only confirmed the aberrant DNA methylated regions in the process of preeclampsia reported previously, but also identified unreported regions. A total of 4 selected DMRs (Differentially Methylated Regions) were also confirmed by MassARRAY EppiTYPER. Of these, PTPRN2, which had low level of 5-mC and high level of 5-hmC at gene body, was further verified to have lower methylation level at promoter regions in case group compared with controls. In conclusion, our study provided genome-wide distribution of 5-mC and 5-hmC in severe PE and normal controls, which have further clinical value for the identification of diagnostic and therapeutic markers for severe PE.

2014-12-13 | GSE63743 | GEO

Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain

Project description:5-Hydroxymethylcytosine (hmC) is particularly abundant in mammalian brains with yetto be revealed functions. Here, we present genome-wide and single-base-resolutionmaps of hmC and mC in the human brain. We demonstrated that hmCs increasemarkedly from the fetal to the adult stage, and in the adult brain, 13.4% of all CpGs arehighly hydroxymethylated with strong enrichment at genic regions and distal regulatoryelements. Notably, hmC peaks were identified at the 5' splicing sites at the exon-intronboundary, suggesting a mechanistic link between hmC and splicing. We also report asurprising transcription-correlated hmC bias toward the sense strand and an mC biastoward the antisense strand of gene bodies. Furthermore, hmC is negatively correlatedwith H3K27me3-marked repressive genomic regions, and is more enriched in poisedenhancers than active enhancers. Our results provide insights into understanding themultiple potential functions of hmC in the human brain. A cell type specific hydroxymethylome sample of NeuN+ neurons in frontal lobe from the same adult individual, whose TAB-Seq data was deposited in GSE46710

2014-02-22 | E-GEOD-55249 | biostudies-arrayexpress

Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain

2014-02-22 | GSE55249 | GEO

Sexual Dimorphism of Preeclampsia-Dysregulated Transcriptomic Profiles and Endothelial Function in Fetal Endothelial Cells

Project description:Preeclampsia-offspring have increased risks of developing cardiovascular disorders in adulthood, implicating that preeclampsia programs fetal vasculature in utero. Fetal sex is associated with the risk of preeclampsia but the underlying mechanisms are unclear. We hypothesize that preeclampsia alters fetal endothelial gene expression and disturbs cytokines and growth factors-induced endothelial function in a fetal sex-specific manner. Methods: RNAseq analysis was performed with female and male unpassaged (P0) human umbilical vein endothelial cells (HUVECs) from normotensive and preeclamptic (PE) pregnancies and verified by RT-qPCR. Results: PE dysregulate 926 and 172 genes in female and male P0-HUVECs, respectively. PE differentially dysregulates cardiovascular diseases (i.e. heart failure) and endothelial function (i.e. endothelial cell migration, calcium, eNOS, and iNOS signaling)-associated genes in female and male P0-HUVECs. PE also differentially dysregulates TNF-, TGFβ1-, FGF2-, and VEGFA-regulated gene networks in female and male P0-HUVECs. Conclusions: There are sexual dimorphisms of PE-dysregulated cardiovascular diseases and endothelial function-associated genes/pathways in fetal endothelial cells in association with sexual dimorphisms of PE-dysregulated fetal endothelial function.

2019-07-02 | GSE116428 | GEO

miRNAs as Common Regulators of the Transforming Growth Factor (TGF)-β Pathway in the Preeclamptic Placenta and Cadmium-treated Trophoblasts: Links between the Environment, the Epigenome and Preeclampsia

Project description:Preeclampsia (PE) is a pregnancy disorder characterized by high blood pressure and proteinuria that can cause adverse health effects in both mother and fetus. There is no current cure for PE other than delivery of the fetus. While the etiology is unknown, poor placentation of the placenta due to aberrant signaling of growth and angiogenic factors has been postulated as causal factors of PE. In addition, environmental contaminants, such as the metal cadmium (Cd), have been linked to placental toxicity and increased risk of developing PE. Here, we use a translational study design to investigate genomic and epigenomic alterations in both placentas and placental trophoblasts, focused on the angiogenesis-associated transforming growth factor-beta (TGF-β) pathway. Genes within the TGF-β pathway displayed increased expression in both the preeclamptic placenta and Cd-treated trophoblasts. In addition, miRNAs that target the TGF-β pathway were also significantly altered within the preeclamptic placenta and Cd-treated trophoblasts. Integrative analysis resulted in the identification of a subset of Cd-responsive miRNAs, including miR-26a and miR-155, common to preeclamptic placentas and Cd-treated trophoblasts. These miRNAs have previously been linked to PE and are predicted to regulate members of the TGF-β pathway. Results from this study provide future targets for PE treatment.

2016-07-12 | GSE84260 | GEO

Mast cell-derived SAMD14 is a novel regulator of the human prostate tumor microenvironment

Project description:Mast cells (MCs) are important cellular components of the tumor microenvironment and are significantly associated with poor patient outcomes in prostate cancer and other solid cancers. The promotion of tumor progression partly involves heterotypic interactions between MCs and cancer-associated fibroblasts (CAFs) which combine to potentiate a pro-tumor extracellular matrix and promote epithelial cell invasion and migration. Thus far, the interactions between MCs and CAFs remains poorly understood. To identify molecular changes that may alter resident MC function in the prostate tumor microenvironment, we profiled the transcriptome of human prostate MCs, isolated from patient-matched non-tumor and tumor-associated regions of fresh radical prostatectomy tissue. Transcriptomic profiling revealed a distinct gene expression profile of MCs isolated from prostate tumor regions, including the downregulation of SAMD14, a putative tumor suppressor gene. Proteomic profiling revealed overexpression of SAMD14 in HMC-1 MCs altered the secretion of proteins associated with immune regulation and extracellular matrix processes. To assess MC biological function within a model of the prostate tumor microenvironment, HMC-1-SAMD14+ conditioned media was added to co-cultures of primary prostatic CAFs and prostate epithelium. HMC-1-SAMD14+ secretions were shown to reduce the deposition and alignment of matrix produced by CAFs and suppress pro-tumorigenic prostate epithelial morphology. Overall, our data presents the first profile of human MCs derived from patient prostate cancer specimens and identifies MC-derived SAMD14 as an important mediator of MC phenotype and function within the prostate tumor microenvironment.

2021-03-12 | PXD022782 | Pride

Effect of Hypoxia in Severe Preeclampsia through Epigenetic Regulation

Project description:Though the pathophysiology of preeclampsia (PE) is unclear worldwide, placental hypoxia has been implicated in the pathologic processes of PE.In this study, we profiled the transcriptome in BeWo and JEG-3 cells cultured in hypoxic condition or normal ones based on the RNA sequencing dataset. After filtered the low-quality ones, the RNA readers was aligned to human genome hg19 by TopHat and then assembled by Cufflinks. The expression value of each transcript was calculated and consequently differentially expressed genes were screened out. CD39 and ZDHHC14 were found to have both different mRNA in hypoxic cells and abnormal methylation level in severely preeclamptic placentas. The mRNA expression of CD39 and ZDHHC14 in placental tissues were analyzed using qRT-PCR. The differential methylated regions (DMRs) of CD39 and ZDHHC14 were confirmed by MassARRY EppiTYPER. The effect of hypoxia on trophoblast cells was detected with western blotting and enzyme linked immunosorbent assay. The results showed CD39 and ZDHHC14were significantly lower in severe PE placenta, hypoxia significantly reduced the expression of CD39 and ZDHHC14 and the secretion of CD39 in trophoblast cells. Therefore, we believed hypoxia plays an important role in the processes of severe PE via decreasing the expression of CD39 and ZDHHC14 by changing their methylation level in placenta.

2017-08-27 | GSE72437 | GEO

WDR76 promotes MLL-rearranged leukemia via highly-selective binding of 5-hydroxymethylcytosine in DNA

Project description:Although rare, the distribution of the 5-hydroxymethylcytosine (hmC) modification in mammalian DNA is tissue- and gene-specific, yet distinct from its repressive methylcytosine (mC) precursor, suggesting unique functions. To examine this possibility, we fractionated mammalian brain extracts to discover binding partners specific for oxidized states of mC. We demonstrate that one such factor, WDR76, is a highly hmC-specific binding protein that modulates gene expression within chromosomal regions enriched in hmC where it binds. In human cell lines and mouse models, WDR76 recruitment by hmC is critical for the initiation and maintenance of MLL-rearranged leukemias. Beyond its canonical role as an intermediate in mC remediation, we show that hmC can be an epigenetic mark whose recognition drives leukemogenesis, portending analogous signaling pathways for other rare DNA modifications.

2021-01-06 | GSE108832 | GEO

Integrated analysis of the transcriptome-wide m6A methylome in preeclampsia and healthy control placentas

Project description:N6-methyladenosine (m6A) is the most prevalent modification in eukaryotic mRNA and potential regulatory functions of m6A have been shown by mapping the RNA m6A modification landscape. M6A modification in active gene regulation manifests itself as altered methylation profiles. However, the profiling of m6A modification and its potential role in preeclampsia (PE) has not yet been studied. In this work, placental samples were collected from PE and control patients. MeRIP-seq was performed to identify differences in m6A methylatio. Altered peaks of m6A-modified transcripts were primarily associated with nitrogen compound metabolic process, positive regulation of vascular-associated smooth muscle cell migration, and endoplasmic reticulum organisation. The m6A hyper-methylated genes of Wnt/β-catenin signalling pathway, mTOR signalling pathway, and several cancer-related pathways may contribute to PE. Our data provide novel information regarding m6A modification alterations in PE and help our understanding of the pathogenesis of PE.

2020-08-24 | GSE143966 | GEO

Quantification of calcyclin and heat shock protein 90 in sera from women with and without preeclampsia by mass spectrometry

Project description:Maternal serum levels of calcyclin and heat shock protein 90 were compared throughout pregnancy from the first trimester till term among women with preeclampsia (PE) and age-matched normotensive pregnant controls (C). Serum samples from two different studies, a nested case-control study embedded in the Rotterdam periconception cohort and the Lepra Study both conducted at the Erasmus MC in Rotterdam. They were collected in the first, second and third trimester of pregnancy in 43 patients with preeclampsia, consisting of 20 early-onset and 23 late-onset preeclampsia, and 46 normotensive pregnant controls. A serum based 2D LC-MS assay on Parallel Reaction Monitoring mode using a high resolution tribrid mass spectrometer was used to quantify both calcyclin and heat shock protein 90.

2018-11-21 | PXD009025 | Pride

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