The alteration of 5-hydroxymethylcytosine modification contributes to ischemic brain injury [5hmC-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE67188 | GEO | 2015/09/08
SECONDARY ACCESSION(S): PRJNA279208
REPOSITORIES: GEO
Similar Datasets
Project description:Epigenetic modifications, such as cytosine methylation and histone modification, have been shown involved in the pathology of ischemic brain injury. Recent works have implicated 5-hydroxymethylcytosine (5hmC), a DNA base derived from 5-methylcytosine (5mC) through the oxidation by Ten-Eleven Translocation (TET) enzymes, in DNA methylation-related plasticity. In this study we show that 5hmC abundance could be induced to increase by ischemia injury. Genome-wide profiling of 5hmC identified differentially hydroxymethylated regions (DhMRs) associated with ischemic injury and DhMRs were found enriched among the genes involved in cell junction, neuronal morphogenesis and neurodevelopment. These data together suggest that 5hmC modification could serve as a potential therapeutic target for the treatment of ischemic stroke. To determine the genome-wide 5hmC distribution in both ischemic injury (I/R) and control mice (C57BL/6), we employed a previously established chemical labeling and affinity purification method, coupled with high-throughput sequencing (Song et al, Nature Biotechnology, 2011). The ischemic or matched control brain tissues from three pairs of ischemic mice and control mice were used for the analyses.
2015-09-08 | E-GEOD-67188 | biostudies-arrayexpress
Project description:Multiple factors, including molecular, genetic, and epigenetic changes, have been linked to gastric cancer formation and progression. Cytosine methylation (5mC) has been well studied and recognized as a critical epigenetic mark in the mammalian genome. The recent novel discovery of 5-hydroxymethylcytosine (5hmC), which generated by ten-eleven translocation (TET) enzymes, provide new perspective to understand DNA methylation-related plasticity. Here we show that gastric tumors display significant loss of 5hmC. Using matched distant normal, peripheral and tumor primary tissues, we performed genome-wide profiling of 5hmC and identified differentially hydroxymethylated regions (DhMRs) specifically associated with gastric tumors. Gene Ontology (GO) analyses indicated that DhMRs (both loss-of-5hmC and gain-of-5hmC) were enriched among the genes involved in specific pathways. Interestingly the binding motif of hypoxia-inducible factor 1 (HIF1) is enriched among both peripheral and tumor DhMRs, while the Myc-binding motif is specifically enriched among only tumor DhMRs. Tumor progression analyses revealed a unique set of DhMRs that correlate with tumor progression. These data together suggest that the alteration of 5hmC could potentially contribute to the tumorigenesis of gastric tumors.
2019-12-09 | GSE134927 | GEO
Project description:Preeclampsia and gestational diabetes mellitus (GDM) are two of the most common clinical conditions during pregnancy that could result in adverse utero environments of the fetus. Fetal exposure to poor environments in uterus also raises the risk of future adulthood disorders known as fetal origins of adult disease (FOAD). Epigenetic modifications like cytosine methylation and histone modification have been proposed to be involved in FOAD. Recent research has implicated 5-hydroxymethylcytosine (5hmC), a DNA base derived from 5-methylcytosine (5mC) via oxidation by ten-eleven translocation (Tet) enzymes, in DNA methylation-related plasticity. Here we show that the expression of Tet2 and 5hmC abundance significantly altered in the umbilical vessels of preeclampsia. Genome-wide profiling of 5hmC revealed differentially hydroxymethylated regions (DhMRs) associated with preeclampsia and GDM, and DhMRs were enriched among the genes involved in unique biological pathways for each condition. In particular, 5hmC significantly changed in selective transposons and led to the alteration of transposon activity in preeclampsia. The 5hmC-mediated alteration of transposon activity was further confirmed using established hypoxia cell culture model and could be rescued by Vitamin C, a known activator of Tet proteins. Together our results suggest that adverse utero environments induced by preeclampsia could influence 5hmC-mediated epigenetic profile and contribute to FOAD.
2016-05-09 | GSE75941 | GEO
Project description:Medulloblastoma (MB) is the most common malignant brain tumor in children and most of its morbidity is caused by relapse or metastasis. Genome-wide 5-hydroxymethylcytosine (5hmC) decrease has been recognized as one of hallmarks for many malignant tumors. Here we show the dramatic decrease of 5hmC abundance in MB, but with wide variations (p<0.001). Genome-wide 5hmC profiling indicates the acquisition of 5hmC at the genomic loci involved in the Notch signaling pathway. Differentially hydroxymethylated genomic regions (DhMRs) in tumor tissues showed similar features with fetus, but not adult, suggesting that DhMRs in tumor prevent tumor from differentiation for normal brain development. By combining the 5hmC abundance and the postoperative survival of the patients, we found that the decrease of 5hmC could serve as a marker and unfavorable prognosis indicator of MB. These results indicate a potential important role of 5hmC in MB.
2021-04-06 | GSE74336 | GEO
Project description:The most widely utilized approaches for quantifying DNA methylation involve the treatment of genomic DNA with sodium bisulfite, although this method cannot distinguish between DNA methylation (5mC) and DNA hydroxymethylation (5hmC). Previous studies have shown that 5hmC is enriched in the brain, although little is known about its genomic distribution and how it differs between anatomical regions and individuals. In this study, we combined oxidative bisulfite (oxBS) treatment with the Illumina Infinium 450K BeadArray to quantify genome-wide patterns of 5hmC in two distinct anatomical regions of the brain (prefrontal cortex and cerebellum) dissected from multiple individuals. We identified 37,145 and 65,563 sites passing our threshold for detectable 5hmC in the prefrontal cortex and cerebellumm, respectively, with 23,445 loci common across both brain regions. Distinct patterns of 5hmC were identified in each brain region, with notable differences in the genomic location of the most hydroxymethylated loci between these brain regions. Tissue-specific patterns of 5hmC were subsequently confirmed in an independent set of prefrontal cortex and cerebellum samples. Our data are available as downloadable UCSC genome browser tracks (http://epigenetics.iop.kcl.ac.uk/HMC/) as a resource to the community. Our study represents the first systematic analysis of 5hmC in the human brain, identifying tissue-specific hydroxymethylated positions and genomic regions characterized by inter-individual variation in DNA hydroxymethylation. This study demonstrates the utility of combining oxBS-treatment with the Illumina 450k methylation array to systematically quantify 5hmC across the genome and the potential utility of this approach for epigenomic studies of brain disorders.
2015-11-30 | GSE74368 | GEO
Project description:Autism spectrum disorders (ASD) comprise a group of disorders characterized by impaired language, social, and communication skills, in addition to restrictive behaviors or stereotypies. However, with a prevalence of 1.5% in developed countries and relatively high comorbidity rates, no clear underlying mechanism that unifies the heterogeneous phenotypes of ASD is known. 5-hydroxymethylcytosine (5hmC) has been reported highly enriched in brain, and is now recognized as an important epigenetic mark in developmental and neurological disorders. To explore the role of 5hmC in ASD, we utilized the genomic DNA isolated from the postmortem cerebellum of both ASD patients and age-matched controls to profile genome-wide distribution of 5hmC. We identified 797 age-dependent differential hydroxymethylated regions (DhMRs) (q-value < 0.05, FDR adjusted) in young group (age ≤ 18), while no significant DhMR was identified in the groups over 18-year-old. Pathway and disease association analyses indicated that the intragenic DhMRs were located in the genes that involved in cell-cell communication and neurological disorders. By comparing the 5hmC counts (ASD vs. Control) in each psychiatric gene (±10kb), we observed significant 5hmC changes in larger fraction of psychiatric genes than in reference genes. Interestingly, we found that the predicted cis functions of non-coding intergenic DhMRs strikingly associated with ASD and intellectual disorders. A significant fraction of intergenic DhMRs were overlapped with topologically associating domains (TAD). These results together suggest that 5hmC dynamic alteration is associated with ASD, particularly in the early development stage, and could contribute to the pathogenesis of ASD.
2018-05-26 | GSE107012 | GEO
Project description:DNA hydroxymethylation (5hmC) represents a new layer of epigenetic regulation in addition to DNA methylation (5mC). The genome-wide patterns of 5hmC distribution in many tissues and cells have recently been revealed by hydroxymethylated DNA immunoprecipitation (hMeDIP) followed by high throughput sequencing or tiling arrays. However, the DNA hydroxymethylome data generated by the conventional hMeDIP-seq method can not be used for direct quantitative comparison across different samples. In this study, we report a new quantitative hMeDIP-seq method, which uses barcode technology to label different DNA samples and performs hMeDIP-seq for multiple samples in one reaction system. Using this new method, we profiled and compared the DNA hydroxymethylomes of mouse ES cells (ESCs) and mouse ESCs-derived neural progenitor cells (NPCs). 5hmC levels around TSS in either ESCs or NPCs had negative correlation with gene expression levels，while 5hmC levels at gene body regions had different correlation with gene expression, depending on cell types. We identified differential hydroxymethylated regions (DHMRs) by comparing the 5hmC density of all 5hmC peaks between ESCs and NPCs. Many selected DHMRs (e.g., Ankrd23, Hist1h2aa, Fbxw7, and Epha2) were validated by hMeDIP-qPCR. Furthermore, we analyzed the relationship between the alteration of DNA hydroxymethylation and the gene expression change during neural differentiation, and our data suggest that both up- and down-regulated genes exhibited dramatic decrease in 5hmC during neural differentiation while the alteration of 5hmC had weak positive correlation with the changes in gene expression. Taken together, our data demonstrate that quantitative hMeDIP-seq is a powerful approach for genome-wide comparison of DNA hydroxymethylation across multiple samples. Importantly, the DHMRs between ESCs and NPCs uncovered in this study may provide clues for further investigation of the function of 5hmC in gene regulation and neural differentiation. Comparision of the genome-wide distribution of 5hmC in mouse embryonic stem cells and mouse ES-derived neural progenitor cells.
2013-03-08 | E-GEOD-40810 | biostudies-arrayexpress
Project description:Enhancers are developmentally-controlled transcriptional regulatory regions whose activities are modulated through histone modifications or histone variant deposition. Here, we show by genome-wide mapping that the newly discovered DNA modification 5-hydroxymethylcytosine (5hmC) is dynamically associated with transcription factor binding to distal regulatory sites during neural differentiation of mouse P19 cells as well as during adipocyte differentiation of mouse 3T3-L1 cells. Functional annotation reveals that regions gaining 5hmC are associated with genes expressed either in neural tissues when P19 cells undergo neural differentiation or in adipose tissue when 3T3-L1 cells undergo adipocyte differentiation. Furthermore, distal regions gaining 5hmC together with H3K4me2 and H3K27ac in P19 cells behave as differentiation-dependent transcriptional enhancers. Identified regions are enriched in motifs for transcription factors regulating specific cell fates like Meis1 in P19 cells and PPARgamma in 3T3-L1 cells. Accordingly, a fraction of hydroxymethylated Meis1 sites were associated with a dynamic engagement of the 5mC hydroxylase Tet1. In addition, kinetic studies of cytosine hydroxymethylation of selected enhancers indicated that DNA hydroxymethylation is an early event of enhancer activation. Hence, acquisition of 5hmC in cell-specific distal regulatory regions may represent a major event of enhancer progression toward an active state and participate in selective activation of tissue-specific genes Genome-wide 5hmC distribution was determined using hMeDIP-seq. Cells used in this study are P19.6 mouse embryonal carnicoma cells and P19.6 cells treated for 48 hours with 1M-BM-5M all-trans retinoic acid (RA), as well as 3T3-L1 cells and 3T3-L1 derived adipocytes differentiated with dexamethasone, insulin and IBMX (differentiation cocktail - DC). Individual hMeDIP samples from P19.6 ord 3T3-L1 cells were pooled for library preparation. Libraries were prepared and sequenced at the IBL sequencing facility (Lille, France) with an Illumina Genome Analyser II.
2012-06-04 | E-GEOD-38407 | biostudies-arrayexpress
Project description:Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder in which patients carry premutation alleles of 55-200 CGG repeats on the FMR1 gene. To date, whether alterations in epigenetic regulation modulate FXTAS has gone unexplored. 5-hydroxymethylcytosine (5hmC) converted from 5-methylcytosine (5mC) by the ten-eleven translocation (TET) family of proteins, has been found recently to play key roles in neuronal functions. Here we undertook genome-wide profiling of cerebellar 5hmC in a FXTAS mouse model (rCGG mice) and found that rCGG mice at 16 weeks showed overall reduced 5hmC levels genome-wide compared to age-matched wild-type littermates. However, we also observed gain-of-5hmC regions in repetitive elements, as well as cerebellum-specific enhancers, but not general enhancers. Genomic annotation and motif prediction of wild-type- and rCGG-specific differential 5-hydroxymethylated regions (DhMRs) revealed their high correlation with genes and transcription factors that are important in neuronal developmental and functional pathways. DhMR-associated genes partially overlapped with genes that were differentially associated with ribosomes in CGG mice identified by bacTRAP ribosomal profiling. Taken together, our data strongly indicate a functional role for 5hmC-mediated epigenetic modulation in the etiology of FXTAS, possibly through the regulation of transcription. Examination genome-wide 5hmC in FXTAS mice model
2013-10-17 | E-GEOD-49463 | biostudies-arrayexpress
Project description:DNA methylation in murine WT ES cells was investigated by MBD domain mediated pull down of methylated DNA followed by chip analysis. For examination of 5hmC, hydroxymethylated DNA was enriched by Click-chemistry mediated pull down. Because of the lower amount of 5hmC, two different approached were adopted. The first approach was based on direct labeling of 5hmC DNA, and in the second method DNA was labeled after amplification with vitro transcription (IVT) . Microarray based hybridization (chip) analysis of epigenetic modifications, namely, 5mC and 5hmC for murine WT ES cells.
2014-10-21 | E-GEOD-51473 | biostudies-arrayexpress