Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA301557 | ENA |
REPOSITORIES: ENA
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Project description:The methyl binding domain 3 (MBD3) family proteins promote Tet2 enzymatic activity for mediating 5mC conversion
| PRJNA301898 | ENA
Project description:The methyl binding domain 3 (MBD3) family proteins promote Tet2 enzymatic activity for mediating 5mC conversion [HTS]
| PRJNA301900 | ENA
Project description:Ten-eleven translocation (TET) proteins are key players involved in the dynamic regulation of cytosine methylation and demethylation. Inactivating mutations of TET2 are frequently found in human malignancies, highlighting the essential role of TET2 in cellular transformation. However, the factors that control TET enzymatic activity remain largely unknown. Here we found that MBD3 and its analogue MBD3L2 can specifically modulate the enzymatic activity of Tet2 protein, but not Tet1 and Tet3 proteins, in converting 5mC into 5hmC. Moreover, MBD3L2 is more effective than MDB3 in promoting Tet2 enzymatic activity via strengthening the binding affinity between Tet2 and the methylated DNA target. Further analysis revealed pronounced decreases in 5mC levels at MBD3L2 and Tet2 co-occupied genomic regions, most of which are promoter elements associated with either cancer-related genes or genes involved in the regulation of cellular metabolic processes. Our data add new insights into the regulation of Tet2 activity by MBD3 and MBD3L2 in modulating its target gene activities in cancer development and have important applications in understanding how dysregulation of TET2 may contribute to human malignancy.
2016-03-03 | GSE74914 | GEO
Project description:Ten-eleven translocation (TET) proteins are key players involved in the dynamic regulation of cytosine methylation and demethylation. Inactivating mutations of TET2 are frequently found in human malignancies, highlighting the essential role of TET2 in cellular transformation. However, the factors that control TET enzymatic activity remain largely unknown. Here we found that MBD3 and its analogue MBD3L2 can specifically modulate the enzymatic activity of Tet2 protein, but not Tet1 and Tet3 proteins, in converting 5mC into 5hmC. Moreover, MBD3L2 is more effective than MDB3 in promoting Tet2 enzymatic activity via strengthening the binding affinity between Tet2 and the methylated DNA target. Further analysis revealed pronounced decreases in 5mC levels at MBD3L2 and Tet2 co-occupied genomic regions, most of which are promoter elements associated with either cancer-related genes or genes involved in the regulation of cellular metabolic processes. Our data add new insights into the regulation of Tet2 activity by MBD3 and MBD3L2 in modulating its target gene activities in cancer development and have important applications in understanding how dysregulation of TET2 may contribute to human malignancy.
2016-03-03 | GSE74794 | GEO
Project description:The TET family of dioxygenases catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), but their involvement in establishing normal 5mC patterns during mammalian development and their contributions to aberrant control of 5mC during cellular transformation remains largely unknown. We depleted TET1, TET2, and TET3 by siRNA in a pluripotent embryonic carcinoma cell model and examined the impact on genome-wide 5mC and 5hmC patterns. TET1 depletion yielded widespread reduction of 5hmC, while depletion of TET2 and TET3 reduced 5hmC at a subset of TET1 targets suggesting functional co-dependence. TET2 or TET3-depletion also caused increased 5hmC, suggesting they play a major role in 5hmC removal. All TETs prevent hypermethylation throughout the genome, a finding dramatically illustrated in CpG island shores, where TET depletion resulted in prolific hypermethylation. Surprisingly, TETs also promote methylation, as hypomethylation was associated with 5hmC reduction. TET function was highly specific to chromatin environment: 5hmC maintenance by all TETs occurred at polycomb-marked chromatin and genes expressed at moderate levels; 5hmC removal by TET2 is associated with highly transcribed genes enriched for H3K4me3 and H3K36me3. Importantly, genes prone to hypermethylation in cancer become depleted of 5hmC with TET deficiency, suggesting the TETs normally promote 5hmC at these loci, and all three TETs are required for 5hmC enrichment at enhancers, a condition necessary for expression of adjacent genes. These results provide novel insight into the division of labor among TET proteins and reveal an important connection of TET activity with chromatin landscape and gene expression. Methylation and hydroxymethylation profiling by affinity-based high throughput sequencing
2014-06-14 | E-GEOD-51902 | biostudies-arrayexpress
Project description:The TET family of dioxygenases catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), but their involvement in establishing normal 5mC patterns during mammalian development and their contributions to aberrant control of 5mC during cellular transformation remains largely unknown. We depleted TET1, TET2, and TET3 by siRNA in a pluripotent embryonic carcinoma cell model and examined the impact on genome-wide 5mC and 5hmC patterns. TET1 depletion yielded widespread reduction of 5hmC, while depletion of TET2 and TET3 reduced 5hmC at a subset of TET1 targets suggesting functional co-dependence. TET2 or TET3-depletion also caused increased 5hmC, suggesting they play a major role in 5hmC removal. All TETs prevent hypermethylation throughout the genome, a finding dramatically illustrated in CpG island shores, where TET depletion resulted in prolific hypermethylation. Surprisingly, TETs also promote methylation, as hypomethylation was associated with 5hmC reduction. TET function was highly specific to chromatin environment: 5hmC maintenance by all TETs occurred at polycomb-marked chromatin and genes expressed at moderate levels; 5hmC removal by TET2 is associated with highly transcribed genes enriched for H3K4me3 and H3K36me3. Importantly, genes prone to hypermethylation in cancer become depleted of 5hmC with TET deficiency, suggesting the TETs normally promote 5hmC at these loci, and all three TETs are required for 5hmC enrichment at enhancers, a condition necessary for expression of adjacent genes. These results provide novel insight into the division of labor among TET proteins and reveal an important connection of TET activity with chromatin landscape and gene expression. Affymetrix gene expression Human ST1.0 microarray of NCCIT human embryonic carcinoma cells (4 samples in duplicate).
2014-06-14 | E-GEOD-51901 | biostudies-arrayexpress
Project description:The conversion of 5-methylcytosine (5mC) into 5-Hydroxymethylcytosine (5hmC) by ten-eleven translocation (Tet) family has recently been identified as a key process for active DNA demethylation, whose effects in the immune response is currently unknown. Examination of both 5mC and 5hmC modifications in 5 Th cell types. CD2(Cre)Tet2(f/f) mice (previously described in Moran-Crusio et al.,2011) and wild-type littermates on the mixed background were used in experiments.
2015-04-12 | E-GEOD-49139 | biostudies-arrayexpress
Project description:The conversion of 5-methylcytosine (5mC) into 5-Hydroxymethylcytosine (5hmC) by ten-eleven translocation (Tet) family has recently been identified as a key process for active DNA demethylation, whose effects in the immune response is currently unknown. We used microarrays to characterize the regulation of Tet2 in T cells. We found that deletion of the Tet2 gene in T cells decreased expression of effector cytokines such as IFN-?, IL-17, and IL-10. To analyze the regulation of Tet2 in Th subset differentation, CD2(Cre)Tet2(f/f) mice were used to derive Tet2-deficient Th1 and Th17 cells, and Tet2(f/f) mice were used for Tet2-enriched Th1 and Th17 cells.
2015-04-12 | E-GEOD-48657 | biostudies-arrayexpress
Project description:Methyl CpG binding domain 3 (Mbd3) protein belongs to the MBD family of proteins, responsible for reading the DNA methylation pattern. MBD family proteins bind the methyl-CpG domain and are also involved in heterochromatin formation. Mbd3 protein does not have the ability to selectively recognize methyl-CpG islands, however, its characteristic feature is the ability to bind to 5-hydroxymethylcytosine and unmethylated DNA. Little is known about the role of Mbd3 in epilepsy and epileptogenesis. Our previous study (Bednarczyk et al., 2016) showed an increase in levels of NuRD complex proteins, including Mbd3 protein, in the brain of epileptic animals in a rat model of temporal epilepsy induced by electrical stimulation of the amygdala. Amygdala stimulation induced the binding of NuRD complex containing MBD3 to larger number of regions of DNA. In the present study, we investigated whether the Mbd3 protein is involved in the determination of the seizure threshold. An increase in Mbd3 protein levels was demonstrated in the entorhinal cortex/amygdala in the rat’s brain 4 hours after pentylenetetrazole (PTZ)-induced seizures. No alterations in MBD3 protein levels were detected in hippocampus and somatosensory cortex. No alterations in MBD3 mRNA expression were observed at any time point in any studied brain area. Reduction of Mbd3 level using AAV vector coding shRNA against Mbd3 injected to the amygdala prolonged the latency time to the onset of an acute seizure in PTZ challenge test indicating increase in seizure threshold. This was accompanied by increased anxiety in the open field test. In the contrast, an overexpression of Mbd3 using AAV decreased anxiety and increased their excitability in the open field test. Moreover Mbd3 overexpression in the amygdala accelerated epileptogenesis in the PTZ-kindling model. In order to identify the role of Mbd3 protein in the regulation of gene expression, mRNA profiling with RNA-seq was performed in a model of magnesium deficiency-induced epileptiform discharges in vitro. Mbd3 overexpression in vitro induced changes in gene expression in a time- and state-specific manner. Our data indicate the pro-epileptic properties of the Mbd3 protein in vivo and in vitro.
2024-02-09 | GSE227084 | GEO
Project description:The conversion of 5-methylcytosine (5mC) into 5-Hydroxymethylcytosine (5hmC) by ten-eleven translocation (Tet) family has recently been identified as a key process for active DNA demethylation, whose effects in the immune response is currently unknown. We used microarrays to characterize the regulation of Tet2 in T cells. We found that deletion of the Tet2 gene in T cells decreased expression of effector cytokines such as IFN-γ, IL-17, and IL-10.
2015-04-12 | GSE48657 | GEO