DNA hypohydroxymethylation in pediatric brain tumors is associated with CTCF binding sites and reduced survival
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE152561 | GEO | 2021/06/01
REPOSITORIES: GEO
Similar Datasets
Project description:5-hydroxymethylcytosines (5hmC) is particularly abundant in mammalian brain with little-known functions. Here we present the first genome-wide and single-base-resolution maps of 5hmC and 5mC in human brain by combined application of TAB-Seq and MethylC-Seq. We report that the majority of modified cytosines are hydroxymethylated in adult human brain, a significant proportion of which are highly-hydroxymethylated with enrichment in active genic regions and distal-regulatory elements. 5hmC is more enriched in poised than active enhancers, and CpG island shores and enhancers show comparable 5hmC profiles. Notably, 5hmC spikes were identified at the 5’ splicing sites, suggesting a link between 5hmC and splicing. Additionally, we identified a transcription-correlated 5hmC bias towards to sense strand and a 5mC bias towards antisense strand of gene bodies, and a bias towards C-rich sequences surrounding the 5hmC sites. Our data imply multiple roles for 5hmC in alternative splicing and gene regulation in addition to be an intermediate of DNA demethylation in human brain. Examination of hydroxymethylomes of 1 adult and 1 fetal brain tissue of frontal lobe, as well as 1 methylome of the same adult.
2014-02-14 | E-GEOD-46710 | biostudies-arrayexpress
Project description:5-hydroxymethylcytosines (5hmC) is particularly abundant in mammalian brain with little-known functions. Here we present the first genome-wide and single-base-resolution maps of 5hmC and 5mC in human brain by combined application of TAB-Seq and MethylC-Seq. We report that the majority of modified cytosines are hydroxymethylated in adult human brain, a significant proportion of which are highly-hydroxymethylated with enrichment in active genic regions and distal-regulatory elements. 5hmC is more enriched in poised than active enhancers, and CpG island shores and enhancers show comparable 5hmC profiles. Notably, 5hmC spikes were identified at the 5’ splicing sites, suggesting a link between 5hmC and splicing. Additionally, we identified a transcription-correlated 5hmC bias towards to sense strand and a 5mC bias towards antisense strand of gene bodies, and a bias towards C-rich sequences surrounding the 5hmC sites. Our data imply multiple roles for 5hmC in alternative splicing and gene regulation in addition to be an intermediate of DNA demethylation in human brain.
2014-02-14 | GSE46710 | 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: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: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 A 6-chip study aiming to characterize regulated genes in P19.6 mouse embryonal carcinoma cells following 48 hours treatment with 1M-BM-5M all-trans retinoic acid. RNAs were prepared from three independent triplicate experiments.
2012-06-03 | E-GEOD-27334 | biostudies-arrayexpress
Project description:We investigated genome-wide analysis of 5-hydroxymethylcytosine (5hmC) distribution in mouse intestinal stem and differentiated cells using hydroxyMethylated DNA immunoprecipitation (hMeDIP) followed by sequencing. Genomic DNA from mouse intestinal stem (Lgr5+) and villus differentiated cells were sonicated, immunoprecipitated by a 5hmC antibody, and sequenced in order to identify differential hydroxymethylated regions and genes.
2016-11-23 | E-MTAB-5202 | 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: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 MEIS1 and H3K27ac genome-wide distributions were determined using ChIP-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). ChIP samples were done by SM-CM-)randour A.A. Libraries were prepared and sequenced by the IGBMC sequencing facility (Strasbourg, France) by an Illumina Genome Analyzer II.
2012-06-04 | E-GEOD-33067 | biostudies-arrayexpress
Project description:The two most prevalent types of spinal ependymal tumors are myxopapillary ependymomas (MPE) and spinal ependymomas (SP-EPN). Based on molecular data from bulk tumor samples, we previously identified clinically relevant subtypes with poor (MPE-A; SP-EPN-A) and favorable progression-free survival (MPE-B; SP-EPN-B). However, detailed cellular compositions, molecular heterogeneity, and features of tumor progression are largely unknown. We performed single nucleus transcriptomic sequencing of 25 formalin-fixed and paraffin-embedded spinal ependymal tumors including all MPE and SP-EPN subtypes as well as six paired primary and relapsed MPE-A. Ependymoma subtypes presented with a broad, but comparable tumor microenvironment. Furthermore, neoplastic cells demonstrated inter- and intratumoral heterogeneity regarding cancer cell state composition. Overall, MPE tumors exhibited a significantly higher abundance of the astrocytic state, whereas a ciliated state was more prevalent in SP-EPN. Also, transcriptome-inferred copy number profiles revealed tumor cell clusters with distinct chromosomal alterations across tumors, suggesting subclonal neoplastic growth. Compared to normal human spinal cord cell populations, MPE tumor cells displayed similarities to astrocytes and ependymal cells, whereas SP-EPN exclusively matched ependymal cells. MPE-A demonstrated a distinct profile, being similar to the roof and floor plate of the developing spinal cord. Paired primary and relapsed MPE-A revealed mostly similar histology, epigenetics, copy number profiles, and cellular composition of neoplastic cells. Single nucleus transcriptomic sequencing provides valuable insights into the molecular composition of spinal ependymoma types and subtypes and may pave the way for a better understanding of tumor evolution and identification of therapeutic targets.
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Project description:The two most prevalent types of spinal ependymal tumors are myxopapillary ependymomas (MPE) and spinal ependymomas (SP-EPN). Based on molecular data from bulk tumor samples, we previously identified clinically relevant subtypes with poor (MPE-A; SP-EPN-A) and favorable progression-free survival (MPE-B; SP-EPN-B). However, detailed cellular compositions, molecular heterogeneity, and features of tumor progression are largely unknown. We performed single nucleus transcriptomic sequencing of 25 formalin-fixed and paraffin-embedded spinal ependymal tumors including all MPE and SP-EPN subtypes as well as six paired primary and relapsed MPE-A. Ependymoma subtypes presented with a broad, but comparable tumor microenvironment. Furthermore, neoplastic cells demonstrated inter- and intratumoral heterogeneity regarding cancer cell state composition. Overall, MPE tumors exhibited a significantly higher abundance of the astrocytic state, whereas a ciliated state was more prevalent in SP-EPN. Also, transcriptome-inferred copy number profiles revealed tumor cell clusters with distinct chromosomal alterations across tumors, suggesting subclonal neoplastic growth. Compared to normal human spinal cord cell populations, MPE tumor cells displayed similarities to astrocytes and ependymal cells, whereas SP-EPN exclusively matched ependymal cells. MPE-A demonstrated a distinct profile, being similar to the roof and floor plate of the developing spinal cord. Paired primary and relapsed MPE-A revealed mostly similar histology, epigenetics, copy number profiles, and cellular composition of neoplastic cells. Single nucleus transcriptomic sequencing provides valuable insights into the molecular composition of spinal ependymoma types and subtypes and may pave the way for a better understanding of tumor evolution and identification of therapeutic targets.
2025-09-12 | GSE298506 | GEO