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Dynamic changes of DNA methylome and hydroxymethylome during neural differentiation of hES cells (Methylation BeadChip)

ABSTRACT: DNA methylation and hydroxymethylation have been implicated in normal development and differentiation, but our knowledge about the genome-wide distribution of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) during cellular differentiation remains limited. Using in vitro model system of gradual differentiation of human embryonic stem (hES) cells into ventral midbrain-type neural precursor (NP) cells and terminally into dopamine (DA) neurons, we explored changes in 5mC or 5hmC patterns during lineage commitment. We used three techniques, 450K DNA methylation array, MBD-seq, and hMeDIP-seq, and found combination of these methods can provide comprehensive information on the genome-wide 5mC or 5hmC patterns. We observed dramatic changes of 5mC patterns during differentiation of hES cells into NP cells. Although genome-wide 5hmC distribution was more stable than 5mC, coding exons, CpG islands and shores showed dynamic 5hmC patterns during differentiation. In addition to the role of DNA methylation as a mechanism to initiating gene silencing, we also found DNA methylation as a locking system to maintain gene silencing. More than 1,000 genes including mesoderm development related genes acquired promoter methylation during neuronal differentiation even though they were already silenced in hES cells. Finally, we found that activated genes lost 5mC in transcription start site (TSS) but acquired 5hmC around TSS and gene body during differentiation. Our findings may provide clues for elucidating the molecular mechanisms underlying lineage specific differentiation of pluripotent stem cells during human embryonic development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE38216 | GEO | 2013/11/04

SECONDARY ACCESSION(S): PRJNA167472

REPOSITORIES: GEO

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Dynamic changes of DNA methylome and hydroxymethylome during neural differentiation of hES cells (Methylation BeadChip)

Project description:DNA methylation and hydroxymethylation have been implicated in normal development and differentiation, but our knowledge about the genome-wide distribution of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) during cellular differentiation remains limited. Using in vitro model system of gradual differentiation of human embryonic stem (hES) cells into ventral midbrain-type neural precursor (NP) cells and terminally into dopamine (DA) neurons, we explored changes in 5mC or 5hmC patterns during lineage commitment. We used three techniques, 450K DNA methylation array, MBD-seq, and hMeDIP-seq, and found combination of these methods can provide comprehensive information on the genome-wide 5mC or 5hmC patterns. We observed dramatic changes of 5mC patterns during differentiation of hES cells into NP cells. Although genome-wide 5hmC distribution was more stable than 5mC, coding exons, CpG islands and shores showed dynamic 5hmC patterns during differentiation. In addition to the role of DNA methylation as a mechanism to initiating gene silencing, we also found DNA methylation as a locking system to maintain gene silencing. More than 1,000 genes including mesoderm development related genes acquired promoter methylation during neuronal differentiation even though they were already silenced in hES cells. Finally, we found that activated genes lost 5mC in transcription start site (TSS) but acquired 5hmC around TSS and gene body during differentiation. Our findings may provide clues for elucidating the molecular mechanisms underlying lineage specific differentiation of pluripotent stem cells during human embryonic development. Examination of genome-wide DNA methylation in 3 cell types (human embryonic stem, neural precursor, and dopamine neuron cells)

2013-11-04 | E-GEOD-38216 | biostudies-arrayexpress

Dynamic changes of DNA methylome and hydroxymethylome during neural differentiation of hES cell (hMeDIP-Seq and MBD-Seq)

Project description:DNA methylation and hydroxymethylation have been implicated in normal development and differentiation, but our knowledge about the genome-wide distribution of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) during cellular differentiation remains limited. Using in vitro model system of gradual differentiation of human embryonic stem (hES) cells into ventral midbrain-type neural precursor (NP) cells and terminally into dopamine (DA) neurons, we explored changes in 5mC or 5hmC patterns during lineage commitment. We used three techniques, 450K DNA methylation array, MBD-seq, and hMeDIP-seq, and found combination of these methods can provide comprehensive information on the genome-wide 5mC or 5hmC patterns. We observed dramatic changes of 5mC patterns during differentiation of hES cells into NP cells. Although genome-wide 5hmC distribution was more stable than 5mC, coding exons, CpG islands and shores showed dynamic 5hmC patterns during differentiation. In addition to the role of DNA methylation as a mechanism to initiating gene silencing, we also found DNA methylation as a locking system to maintain gene silencing. More than 1,000 genes including mesoderm development related genes acquired promoter methylation during neuronal differentiation even though they were already silenced in hES cells. Finally, we found that activated genes lost 5mC in transcription start site (TSS) but acquired 5hmC around TSS and gene body during differentiation. Our findings may provide clues for elucidating the molecular mechanisms underlying lineage specific differentiation of pluripotent stem cells during human embryonic development. Examination of hMeDIP-Seq and MBD-Seq in 3 cell types (human embryonic stem, neural precursor, and dopamine neuron cells)

2013-11-04 | E-GEOD-38214 | biostudies-arrayexpress

Dynamic changes of DNA methylome and hydroxymethylome during neural differentiation of hES cell (hMeDIP-Seq and MBD-Seq)

2013-11-04 | GSE38214 | GEO

Hydroxylation of 5-methylcytosine by TET2 maintains the active state of the mammalian HOXA cluster (Infinium HumanMethylation450 Beadchip)

Project description:Differentiation is accompanied by extensive epigenomic reprogramming, leading to the repression of stemness factors and the transcriptional maintenance of activated lineage-specific genes. Here we used the mammalian Hoxa cluster of developmental genes as a model system to follow changes in DNA modification patterns during retinoic acid induced differentiation. We found the inactive cluster to be marked by defined patterns of 5-methylcytosine (5mC). Upon the induction of differentiation, the active anterior part of the cluster became increasingly enriched in 5-hydroxymethylcytosine (5hmC), following closely the colinear activation pattern of the gene array, which was paralleled by the reduction of 5mC. Depletion of the 5hmC generating dioxygenase Tet2 impaired the maintenance of Hoxa activity and partially restored 5mC levels. Our results indicate that gene specific 5mC-5hmC conversion by Tet2 is crucial for the maintenance of active chromatin states at lineage-specific loci. Genome wide DNA methylation profiling of uninduced and retinoic acid (RA) induced NTera2/D1 embryocarcinoma cells (NT2). Bisulphite converted DNA of uninduced, 7d RA and 14d RA treated NT2 cells were hybridised to the Illumina Infinium HumanMethylation450 Beadchip.

2012-05-02 | E-GEOD-32362 | biostudies-arrayexpress

Modified cytosine binding proteins

Project description:DNA methylation (5mC) plays important roles in epigenetic regulation of genome function, and recently the TET1-3 hydroxylases have been found to oxidize 5mC to hydroxymethylcytosine (5hmC), formylcytosine (5fC), and carboxylcytosine (5caC) in DNA. These derivatives have a role in demethylation of DNA but in addition may have epigenetic signaling functions in their own right. A recent study identified proteins with preferential binding to 5-methylcytosine (5mC) and its oxidized forms where readers for 5mC and 5hmC (5-hydroxymethylcytosine) showed little overlap while further oxidation forms enriched for repair proteins and transcription regulators. We extend this study by using promoter sequences as baits and compare protein binding patterns to unmodified or modified cytosine containing DNA using mouse embryonic stem cell (mESCs) extracts. The dataset contains 3 biological replicates each of mouse ES cell nuclear proteins binding to Pax6 and FGF15 promoter sequences containing different modified forms of cytosine. Data analysis: Mass spectrometric data were processed using Proteome Discoverer v1.3 and searched against a mammalian entries in Uniprot 2011.09 using Mascot v2.3 with the following parameters: Enzyme - trypsin; max 1 missed cleavage; Precursor Mass Tolerance - 10 ppm; Fragment Mass Tolerance - 0.6 Da; Dynamic Modification - Oxidation (M); Static Modification - Carbamidomethyl at C.

2013-10-21 | PXD000524 | Pride

Genome-wide Regulation of 5hmC, 5mC and Gene Expression by Tet1 Hydroxylase in Mouse Embryonic Stem Cells (bisulfite sequencing data)

Project description:DNA methylation of C5-cytosine (5mC) in the mammalian genome is a key epigenetic event that is critical for various cellular processes. However, how the genome-wide 5mC pattern is dynamically regulated remains a fundamental question in epigenetic biology. The TET family of 5mC hydroxylases, which convert 5mC to 5-hydroxymethylcytosine (5hmC), have provided a new potential mechanism for the dynamic regulation of DNA methylation. The extent to which individual Tet family members contribute to the genome-wide 5mC and 5hmC patterns and associated gene network remains largely unknown. Here we report genome-wide mapping of Tet1 and 5hmC in mESCs and reveal a mechanism of action by which Tet1 controls 5hmC and 5mC levels in mESCs. In combination with microarray and mRNA-seq expression profiling, we identify a comprehensive yet intricate gene network influenced by Tet1. We propose a model whereby Tet1 controls DNA methylation both by binding to CpG-rich regions to prevent unwanted DNA methyltransferase activity, and by converting the existing 5mC to 5hmC through its enzymatic activity. This Tet1-mediated antagonism of CpG methylation imparts differential maintenance of DNA methylation status at Tet1 target loci, thereby providing a new regulatory mechanism for establishing the epigenetic landscape of mESCs, which ultimately contributes to mESC differentiation and the onset of embryonic development. To determine the genome-wide DNA methylation changes caused by Tet1 depletion in mouse ES cells. Tet1 protein was depleted by specific siRNA treatment. The DNA methylation levels in control and Tet1 siRNA-transfected ES cells were determined by targeted bisulfite sequencing.

2011-04-21 | E-GEOD-28533 | biostudies-arrayexpress

Genome-wide Regulation of 5hmC, 5mC and Gene Expression by Tet1 Hydroxylase in Mouse Embryonic Stem Cells (bisulfite sequencing data)

2011-04-21 | GSE28533 | GEO

Genome-wide Regulation of 5hmC, 5mC and Gene Expression by Tet1 Hydroxylase in Mouse Embryonic Stem Cells (ChIP-seq data)

2011-04-21 | GSE28532 | GEO

Genome-wide Regulation of 5hmC, 5mC and Gene Expression by Tet1 Hydroxylase in Mouse Embryonic Stem Cells (expression data)

2011-04-21 | GSE28530 | GEO

DNA methylation profiling of human CD4+T-cells in-vitro polarized towards Th1 and Th2 time-series

Project description:Differentiation of CD4+T-cells into effector subsets is a critical component of the adaptive immune system and an incorrect response can lead to autoimmunity or immune deficiency. Cellular differentiation including T-cell differentiation is accompanied by large-scale epigenetic remodeling, including changes in DNA methylation at key regulators of T-cell differentiation. The TET family of enzymes were recently shown to be able to catalyse methylated cytosine (5mC) into 5-hydroxymethylcytosine (5hmC) enabling a pathway of active removal of DNA methylation. Here, we characterize 5hmC, 5mC and transcriptional dynamics during human CD4+T-cell polarisation in a time series approach and relate these changes to profiles in ex-vivo CD4+memory subsets. We observed large-scale remodelling during early CD4+T-cell differentiation which was predictive of subsequent changes during late time points, these changes were also related to disease associated regions which we show can act as functional regulatory elements. This dataset was designed to assess how gene expression changes over time during human CD4+T-cell polarization towards Th1 and Th2. DNA methylation was assessed in relationship to 5hmC levels and changes (see data series), we observed that regions gaining 5hmC early was highly predictive of regions losing DNA methylation during late time points. This submission contains data from the DNA methylation by array profiling of human CD4+T-cells in-vitro polarized towards Th1 and Th2 time-series. It is part of series containing 5hmC and DNA methylation profiling of the same samples. See related experiments E-MTAB-4685, E-MTAB-4686, E-MTAB-4687, E-MTAB-4689.

2016-07-11 | E-MTAB-4688 | biostudies-arrayexpress

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