Postnatal DNA demethylation and its role in tissue maturation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE85251 | GEO | 2018/05/09
REPOSITORIES: GEO
Similar Datasets
Project description:The Arabidopsis thaliana central cell, the companion cell of the egg, undergoes DNA demethylation prior to fertilization, but the targeting preferences and biological significance of this process remain unclear. Here, we show that active DNA demethylation mediated by the DEMETER DNA glycosylase accounts for all of the demethylation in the central cell, and preferentially targets small, AT-rich and nucleosome-depleted transposable elements. The vegetative cell, the companion cell of sperm, also undergoes DEMETER-dependent demethylation of similar sequences, and lack of DEMETER in vegetative cells causes reduced small RNA-directed DNA methylation of transposons in sperm. Our results demonstrate that demethylation in companion cells reinforces transposon methylation in plant gametes, thereby assuring stable silencing of transposable elements across generations Examination of DNA methylation in Arabidopsis endosperm, embryo, and pollen
2012-09-21 | E-GEOD-38935 | biostudies-arrayexpress
Project description:The DNA methylation program is at the bottom layer of the epigenetic regulatory cascade of vertebrate development. While the methylation at C-5 position of the cytosine (C) residues on the vertebrate genomes is achieved through the catalytic activities of the DNA methyltransferases (DNMTs), the conversion of the methylated cytosine (5mC) could be accomplished by the combined actions of the TET enzyme and DNA repair. Interestingly, it has been found recently that the mouse and human DNMTs also possess active DNA demethylation activity in vitro in a Ca2+- and redox condition-dependent manner. We report here the study of tracking down the fate of the methyl group removed from 5mC on DNA during in vitro demethylation reaction by mouse de novo DNMTs, i.e. DNMT3A and DNMT3B. Remarkably, the methyl group becomes covalently linked to the catalytic cysteines utilized by the two de novo DNMTs in their DNA methylation reactions. Thus, the forward and reverse reactions of DNA methylations by the DNMTs may utilize the same cysteine residue(s) as the active site despite of their distinctive pathways. Secondly, we demonstrate that active DNA demethylation of a heavily methylated GFP reporter plasmid by ectopically expressed DNMT3A or DNMT3B occurs in vivo in transfected human HEK 293 cells in culture. Furthermore, the extent of DNA demethylation by the DNMTs in this cell-based system is affected by Ca2+ homeostasis as well as by mutation of their putative active cysteines. These findings substantiate the roles of the vertebrate DNMTs as double-edged swords in DNA methylation-demethylation in vitro as well as in a cellular context.
2022-02-24 | PXD003401 | Pride
Project description:The Arabidopsis thaliana central cell, the companion cell of the egg, undergoes DNA demethylation prior to fertilization, but the targeting preferences and biological significance of this process remain unclear. Here, we show that active DNA demethylation mediated by the DEMETER DNA glycosylase accounts for all of the demethylation in the central cell, and preferentially targets small, AT-rich and nucleosome-depleted transposable elements. The vegetative cell, the companion cell of sperm, also undergoes DEMETER-dependent demethylation of similar sequences, and lack of DEMETER in vegetative cells causes reduced small RNA-directed DNA methylation of transposons in sperm. Our results demonstrate that demethylation in companion cells reinforces transposon methylation in plant gametes, thereby assuring stable silencing of transposable elements across generations
2012-09-21 | GSE38935 | GEO
Project description:Thymic epithelial cells (TECs) begin to develop embryonically in mice and humans, expand in number through puberty, and then stabilize before declining during early adulthood. We identified a mechanism by which TEC numbers and function are maintained postnatally, discovered through a forward genetic screen for altered immune cell development in mice. A viable missense allele (C120Y) of Ovol2 resulted in lymphopenia, in which T cell development was compromised by loss of medullary TECs and dysfunction of cortical TECs. OVOL2 is an essential regulator of epithelial to mesenchymal transition (EMT), and we show that the epithelial identity of TECs is subverted towards a mesenchymal state in OVOL2-deficient mice. We document global changes in chromatin accessibility correlated with gene expression, particularly affecting genes involved in epithelial and mesenchymal cell proliferation and differentiation. OVOL2 regulates chromatin accessibility by inhibiting the BRAF-HDAC complex. In particular, it disrupts the RCOR1-LSD1 complex by directly binding to the lysine demethylase LSD1, resulting in inhibition of LSD1-mediated H3K4me2 demethylation. Thus, OVOL2 controls the epigenetic landscape of TECs, preventing EMT and enforcing TEC identity to support T cell development in the thymus.
2022-12-21 | MSV000090946 | MassIVE
Project description:The vertebrate body plan and organs are shaped during a highly conserved embryonic phase called the phylotypic stage, however the mechanisms that guide the epigenome through this transition and their evolutionary conservation remain elusive. Here we report widespread DNA demethylation of thousands of enhancers during the phylotypic period in zebrafish, Xenopus and mouse. These dynamic enhancers are linked to essential developmental genes that display coordinated transcriptional and epigenomic changes in the diverse vertebrates during embryogenesis. Phylotypic stage-specific binding of Tet proteins to (hydroxy)methylated DNA, and enrichment of hydroxymethylcytosine on these enhancers, implicated active DNA demethylation in this process. Furthermore, loss of function of Tet1/2/3 in zebrafish caused reduced chromatin accessibility and increased methylation levels specifically on these enhancers, indicative of DNA methylation being an upstream regulator of phylotypic enhancer function. Overall, our study reveals a novel regulatory module associated with the most conserved phase of vertebrate embryogenesis and uncovers an ancient developmental role for the Tet dioxygenases.
2016-01-27 | PXD001164 | Pride
Project description:The proposed use of Foxp3+ T-regulatory (Treg) cells as potential cellular therapy in patients with autoimmune diseases, or post-hemopoietic stem cell or organ transplantation, requires a sound understanding of the transcriptional regulation of Foxp3 expression. Conserved CpG dinucleotides in the Treg-specific demethylated region (TSDR) upstream of Foxp3 are demethylated only in stable, thymic-derived Foxp3+ Tregs. Since methyl-binding domain (Mbd) proteins recruit histone-modifying and chromatin-remodeling complexes to methylated sites, we tested whether targeting of Mbd2 might promote demethylation of Foxp3 and thereby promote Treg numbers or function. Surprisingly, while ChIP analysis showed Mbd2 binding to the Foxp3-associated TSDR site in Tregs, Mbd2 targeting by homologous recombination or siRNA decreased Treg numbers and impaired Treg suppressive function in vitro and in vivo. Moreover, we found complete TSDR demethylation in WT Tregs but >75% methylation in Mbd2-/- Tregs, whereas re-introduction of Mbd2 into Mbd2-null Tregs restored TSDR demethylation, Foxp3 gene expression and Treg suppressive function. Lastly, Mbd2-/- Tregs had markedly binding of the DNA demethylase enzyme, Tet2, in the TSDR region. These data show that Mbd2 has a key role in promoting TSDR demethylation, Foxp3 expression and Treg suppressive function. RNA from three independent samples from magnetically separated CD4+CD25+ Treg of MBD2–/– mice, compared to wild type control (all Balb/c background).
2013-09-01 | E-GEOD-48653 | biostudies-arrayexpress
Project description:Following erasure in the early animal embryo, a new bimodal DNA methylation pattern is regenerated at the time of implantation in each individual through a wave of generalized de novo modification with CpG islands specifically left unmethylated. In this paper, we ask whether CpG islands are M-bM-^@M-^\protectedM-bM-^@M-^] from de novo methylation or, alternatively, acquire their unmodified state through M-bM-^@M-^\demethylation.M-bM-^@M-^] Using a genetic approach, we demonstrate that ES cells indeed have the ability to specifically demethylate CpG islands through pathways involving hydroxymethylation (Tet1), deamination (Aid), glycosylation (Mbd4) and excision repair (Gadd45a) genes. Surprisingly, this demethylation system is not actually necessary for generating the overall bimodal methylation pattern in ES cells. This general activity does, however, appear to be involved both in somatic cell reprogramming, as well as the normal methylation reprogramming that takes place in the early embryo. CpG-methylated genomic DNA was enriched using a methyl-DNA immunoprecipitation (mDIP) assay. DNA from the input and bound (enriched) DNA for each sample were labeled and hybridized on the array to define the methylation state of each region.
2013-11-17 | E-GEOD-48923 | biostudies-arrayexpress
Project description:Parent-of-origin-specific (imprinted) gene expression is regulated in Arabidopsis thaliana endosperm by cytosine demethylation of the maternal genome mediated by the DNA glycosylase DEMETER, but the extent of the methylation changes is not known. Here we show that virtually the entire endosperm genome is demethylated, coupled with extensive local non-CG hypermethylation of siRNA-targeted sequences. Mutation of DEMETER partially restores endosperm CG methylation to levels found in other tissues, indicating that CG demethylation is specific to maternal sequences. Endosperm demethylation is accompanied by CHH hypermethylation of embryo transposable elements. Our findings demonstrate extensive reconfiguration of the endosperm methylation landscape that likely reinforces transposon silencing in the embryo. Keywords: Epigenetics; bisulfite sequencing Examination of DNA methylation in four Arabidopsis tissues Description of processed data and raw data file contents can be found in the attached README.txt file
2009-06-16 | E-GEOD-15922 | biostudies-arrayexpress
Project description:We report that the winged helix transcription factor FOXA1 is unexpectedly associated with components of single and double stranded-DNA repair complexes. Biochemical studies and high-throughput approaches validated the hierarchical composition of this FOXA1-nucleated machinery and revealed the dependency on FOXA1 for global targeting of the key repair polymerase POLB. Genome-wide DNA methylomes at single-base resolution demonstrated that FOXA1-DNA repair complex is functionally linked to DNA demethylation in a lineage specific fashion. Loss-of-function studies indicate that a significant portion of FOXA1-bound regions display localized reestablishment of methylation and that the subsets with most consistent hypermethylation are represented by active promoters and enhancers that also exhibit the greatest depletion of POLB following FOXA1 removal. Consistently, forced expression of FOXA1 commits its binding sites to an active DNA demethylation in a POLB dependent manner. Finally, we showed that FOXA1-associated DNA demethylation is tightly coupled with genomic targeting of estrogen receptor and estrogen responsiveness. Together, our results link FOXA1-associated DNA demethylation to its transcriptional pioneering.
2016-06-08 | PXD004271 | Pride
Project description:HBV transcription and replication increases progressively throughout postnatal liver development with maximal viral biosynthesis occurring at around four weeks of age in the HBV transgenic mouse model of chronic infection. Increasing viral biosynthesis is associated with a corresponding progressive loss of DNA methylation. The loss of DNA methylation is associated with increasing levels of 5-hydroxymethylcytosine (5hmC) residues which correlates with increased liver-enriched pioneer transcription factor Forkhead box protein A (FoxA) RNA levels, a rapid decline in postnatal liver DNA methyltransferase (Dnmt) transcripts and a very modest reduction in Ten-eleven translocation (Tet) methylcytosine dioxygenase expression. These observations are consistent with the suggestion that the balance between active HBV DNA methylation and demethylation is regulated by FoxA recruitment of Tet in the presence of declining Dnmt activity. These changes lead to demethylation of the viral genome during hepatocyte maturation with associated increases in viral biosynthesis. Consequently, manipulation of the relative activities of these two counter-balancing processes might permit the specific silencing of HBV gene expression with the loss of viral biosynthesis and the resolution of chronic HBV infections.
2020-12-10 | GSE157451 | GEO