5-hydroxymethylcytosine-mediated epigenetic dynamics during neurodevelopment and aging
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Keith Szulwach
PROVIDER: E-GEOD-32188 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:DNA methylation dynamics influence brain function and are altered in neurological disorders. 5-hydroxymethylcytosine (5-hmC), a DNA base derived from 5-methylcytosine (5mC) accounts for ~40% of modified cytosine in brain, and has been implicated in DNA methylation-related plasticity. Here we map 5-hmC genome-wide across three ages in mouse hippocampus and cerebellum, allowing assessment of its stability and dynamic regulation during postnatal neurodevelopment through adulthood. We find developmentally programmed acquisition of 5-hmC in neuronal cells. Epigenomic localization of 5-hmC-regulated regions reveals stable and dynamically modified loci during neurodevelopment and aging. By profiling 5-hmC in human cerebellum we establish conserved genomic features of 5-hmC. Finally, we implicate 5-hmC in neurodevelopmental disease by finding that its levels are inversely correlated with methyl-CpG-binding protein 2 (Mecp2) dosage, a protein encoded by a gene in which mutations cause Rett Syndrome. These data point toward critical roles for 5-hmC-mediated epigenetic modification in neurodevelopment and diseases. Here we map 5-hmC genome-wide across three ages in mouse hippocampus and cerebellum, allowing assessment of its stability and dynamic regulation during postnatal neurodevelopment through adulthood. Profiling of 5-hmC in human cerebellum we establish conserved genomic features of 5-hmC. Finally, we implicate 5-hmC in neurodevelopmental disease by profiling 5-hmC in mouse cerebellum lacking MeCP2, a protein encoded by a gene in which mutations cause Rett Syndrome.
2011-10-30 | E-GEOD-32050 | biostudies-arrayexpress
Project description:Covalent modification of DNA distinguishes cellular identities and is crucial for regulating the pluripotency and differentiation of embryonic stem (ES) cells. The recent demonstration that 5-methylcytosine (5-mC) may be further modified to 5-hydroxymethylcytosine (5-hmC) in ES cells has revealed a novel regulatory paradigm to modulate the epigenetic landscape of pluripotency. To understand the role of 5-hmC in the epigenomic landscape of pluripotent cells, here we profile the genome-wide 5-hmC distribution and correlate it with the genomic profiles of 11 diverse histone modifications and six transcription factors in human ES cells. By integrating genomic 5-hmC signals with maps of histone enrichment, we link particular pluripotency-associated chromatin contexts with 5-hmC. Intriguingly, through additional correlations with defined chromatin signatures at promoter and enhancer subtypes, we show distinct enrichment of 5-hmC at enhancers marked with H3K4me1 and H3K27ac. These results suggest potential role(s) for 5-hmC in the regulation of specific promoters and enhancers. In addition, our results provide a detailed epigenomic map of 5-hmC from which to pursue future functional studies on the diverse regulatory roles associated with 5-hmC. Genome wide enrichment profile of 5-hmC in H1 human embryonic stem cells
2011-06-24 | E-GEOD-30173 | biostudies-arrayexpress
Project description:Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive deterioration of cognitive function. Evidence suggests a role for epigenetic regulation, in particular the cytosine modifications 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC,) in AD. 5hmC is highly enriched in the nervous system and displays neurodevelopment and age-related changes. To determine the role of 5hmC in AD, we performed genome-wide analyses of 5hmC in DNA from prefrontal cortex of post-mortem AD as well as RNA-Seq to correlate changes in methylation status with transcriptional changes. We also utilized the existing AD fly model to further test the functional significance of these epigenetically altered loci. We identified 325 genes containing differentially hydroxymethylated loci (DhMLs) in both the discovery and replication datasets, and these are enriched for pathways involved in neuron projection development and neurogenesis. Of the 325 genes identified, 140 also showed changes in gene expression by RNA-Seq. Proteins encoded by genes identified in the current analysis form direct protein-protein interactions with AD-associated genes, expanding the network of genes implicated in AD. Furthermore, we identified AD-associated single nucleotide polymorphisms (SNPs) located within or near DhMLs, suggesting that these SNPs may identify regions of epigenetic gene regulation that play a role in AD pathogenesis. Finally using the existing AD fly model we showed that some of these genes could modulate the toxicity associated with AD. Our data implicate neuron projection development and neurogenesis pathways as potential targets in AD. These results indicate that incorporating epigenomic and transcriptomic data with GWAS data can expand the known network of genes involved in disease pathogenesis. Combination of epigenome profiling and Drosophila model enables us to identify the epigenetic modifiers of Alzheimer's disease. University of Kentucky Alzheimer's Disease Research Center (3 control, 3 Alzheimer's) and Emory University Alzheimer's Disease Research Center (2 control, 2 Alzheimer's)
2016-07-20 | E-GEOD-72782 | biostudies-arrayexpress
Project description:5-Methylcytosine (5-mC) is an important DNA modification found in eukaryotes that impacts gene regulation and disease pathogenesis. Recently, 5-hydroxymethylcytosine (5-hmC), another form of DNA modification, has been identified in substantial amounts in certain mammalian cell types; however, its roles as well as its distribution in mammalian genomes are unknown. Here we present a selective chemical labeling method for 5-hmC by utilizing T4 bacteriophage BGT-glucosyltransferase to transfer an engineered glucose moiety containing an azide group onto the hydroxyl group of 5-hmC, which in turn can chemically incorporate a biotin group for detection, affinity enrichment, and sequencing of 5-hmC in mammalian genomes. Using this highly effective method, we demonstrate that 5-hmC is present in human cell lines beyond those previously recognized. We also find a gene expression level-dependent enrichment of intragenic 5-hmC in mouse cerebellum and an age-dependent acquisition of this modification in specific gene bodies linked to neurodegenerative disorders Identification of 5hmC enriched genmoic regions in mouse cerebellum
2010-12-12 | E-GEOD-25398 | biostudies-arrayexpress
Project description:Genome wide of 5-hydroxymethylcytosine profiling of normal and abnormal, and globozoospermia sperm genomes.Two semen samples were collected from a healthy man and a globozoospermia patient who had consulted a physician at ShengJing Hospital of China Medical University. Other semen samples obtained from two volunteers who were good health generally. 5-hmC enriched genomic DNA libraries were generated following the Illumina protocol for M-bM-^@M-^\Preparing Samples for CHIP sequencing of DNAM-bM-^@M-^]. 100bp single end sequencing on Illumina Hiseq2000 to get 5-hmC-enriched DNA fragment sequence was performed. Examination of 5hmC levels in normal, abnormal, and globozoospermia sperm genomes
2013-04-18 | E-GEOD-46135 | biostudies-arrayexpress
Project description:Gene-environment interactions mediated at the epigenetic level may provide an initial step in delivering an appropriate response to environmental changes. 5-hydroxymethylcytosine (5hmC), a DNA base derived from 5-methylcytosine (5mC), accounts for ~40% of modified cytosine in brain and has been implicated in DNA methylation-related plasticity. To identify the role of 5hmC in gene-environment interactions, we exposed both young (6-week-old) and aged (18-month-old) mice to both an enriched environment and a standard environment. Exposure to EE significantly improves learning and memory in aged mice and reduces 5hmC abundance in mouse hippocampus. Furthermore, we mapped the genome-wide distribution of 5hmC and found that the alteration of 5hmC modification occurred mainly at gene bodies. In particular, genes involved in axon guidance are enriched among the genes with altered 5hmC modification. These results together suggest that environmental enrichment could modulate the dynamics of 5hmC in hippocampus, which could potentially contribute to improved learning and memory in aged animals. To identify the role of 5hmC in gene-environment interactions, we exposed both young (6-week-old) and aged (18-month-old) C57B/6 mice to both an enriched environment (EE) and a standard environment. Exposure of mice to EE was achieved by keeping a group of mice in the EE chamber, which is larger than the standard cage, includes novel objects, such as toys of varied color and texture, tunnels, an exercise wheel for voluntary exercise, and extra bedding material, along with free access to food and water. Daily exposure to EE was kept at 5 hours during the daylight cycle for 4 consecutive weeks. Control animals were kept in their small cages that are used as standard housing cages (CE) containing bedding, food and access to water. YC, young mice exposing to control environment, YE, young mice exposing to enriched environment, AC, aged mice exposing to control environment, AE, aged mice exposed to enriched environment. Please note that 5hmC-containing DNA enrichment method was inspired by a unique character of beta-glucotransferase that can specifically add glucose to 5hmC modification. With a modified glucose conjugated with biotin, we are able to purify the 5hmC-containing DNA by biotin-streptavidin-based immunoprecipitation.
2014-09-11 | E-GEOD-61194 | biostudies-arrayexpress
Project description:Mammalian somatic cells can be directly reprogrammed into induced pluripotent stem cells (iPSCs) by introducing defined sets of transcription factors. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem (ES) cells. Human ES cells contain 5-hydroxymethylcytosine (5hmC), which is generated though the oxidation of 5-methylcytosine (5mC) by the TET family of enzymes. Here we show that 5hmC level increases significantly during reprogramming due to the activation of TET1. During this process, dynamic genome-wide 5hmC modification occurs across the genome with more modifications at telomere-proximal regions. Compared with hES cells, we found iPS cells tend to form large-scale (100kb-1.3Mb) aberrant reprogramming hotspots in subtelomeric regions, most of which display incomplete hydroxymethylation. Strikingly, these 5hmC aberrant hotspots largely coincide (>80%) with previously reported aberrant non-CG methylation regions. Our results suggest that 5hmC modification could play important roles during reprogramming to pluripotency, and contribute to the differences between iPSCs and hESCs. we generated comprehensive genome-wide profiles of 5hmC in somatic cells, iPS cell lines derived from a variety of origins, and multiple hES cell lines.
2013-03-21 | E-GEOD-37050 | biostudies-arrayexpress
Project description:Here we used Illumina NGS for high-throughput profiling of the DNA methylome(ERRBS) and hydroxymethylome(hMe-Seal) of primary tumor samples with Acute Myeloid Leukemia(AML). The data can be used to compare hydroxymethylation and methylation patterns from different AML subtypes and normal bone marrow samples. We have sequenced 4 subtypes of AML with hydroxymethylation decrease and 1 subtype with no decrease. We have sequenced 2-5 primary tumor samples for each subtype, and comprated the epigenomic profiles ( ERRBS and hMe-Seal ) of hydroxymethylation deficient subtypes to the control subtype and normal bone marrow samples.
2014-11-20 | E-GEOD-52945 | biostudies-arrayexpress
Project description:Lin28, a well-known RNA-binding protein, regulates diverse cellular properties. All physiological functions of Lin28A characterized so far have been attributed to its repression of let-7 miRNA biogenesis or modulation of the mRNA translational efficiency. Here we show that Lin28A directly binds to a consensus DNA sequence in vitro and in mouse embryonic stem cells in vivo. ChIP-seq and RNA-seq reveal the enrichment of Lin28A binding around transcription start sites, and a positive correlation between its genomic occupancy and expression of many associated genes. Mechanistically, Lin28A recruits 5-methylcytosine-dioxygenase Tet1 to genomic binding sites to orchestrate 5-methylcytosine and 5-hydroxymethylcytosine dynamics. Either Lin28A or Tet1 knockdown leads to dysregulated DNA methylation and expression of common target genes. These results reveal a surprising role for Lin28A in transcriptional regulation via epigenetic DNA modifications and provide a new framework for understanding mechanisms underlying versatile functions of Lin28A in mammalian systems. Examine the DNA binding ability of Lin28 and its roles in regulating gene expression by coordinating with Tet1
2015-12-07 | E-GEOD-74254 | biostudies-arrayexpress
Project description:We generated a genome-wide map of 5hmC in rice panicle using a sensitive chemical labeling method to capture DNA fragments with 5hmC modification, followed by NGS sequencing. We showed that the 5hmC peaks distribution is non-random, about 52% 5hmC was located in gene bodies, 25% in intergenic regions, 11% in promoters, and 12% in immediate downstream. It was significantly enriched in heterochromatic regions of chromosomes 4 and 10, and especially located around TE genes. Combined with RNA-seq transcriptome data, we found that the gene-specific alterations of 5hmC can result in gene activation or repression, suggesting a potential role for 5hmC in gene regulation. From the compared distribution analysis among super-hybrid rice cultivars LYP9, and its parental lines 93-11 and PA64s, we investigated the cultivar-specificity of both the global levels and locus-specific distribution of 5hmC. Our data provided an overview of the genomic distribution of 5hmC in rice panicle. This will set the stage for further functional characterization of this novel DNA modification and its biosynthesis in rice. Examination of 5hmC modifications in rice panicle This submission represents ChIP-Seq component of study.
2014-04-15 | E-GEOD-37242 | biostudies-arrayexpress