TET2 Regulates Mast Cell Differentiation and Proliferation through Catalytic and Non-catalytic Activities.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE70815 | GEO | 2016/05/04
SECONDARY ACCESSION(S): PRJNA289632
REPOSITORIES: GEO
Similar Datasets
Project description:Dioxygenases of the TET family impact genome functions by converting 5-methylcytosine (5mC) in DNA to 5-hydroxymethylcytosine (5hmC). Here, we identified TET2 as a crucial regulator of mast cell differentiation and proliferation. In the absence of TET2, mast cells showed disrupted gene expression and altered genome-wide 5hmC deposition, especially at enhancers and in proximity of down-regulated genes. Impaired differentiation of Tet2-ablated cells could be compensated or further exacerbated by modulating the activity of other TET family members, and mechanistically it could be linked to the dysregulated expression of C/EBP family transcription factors. Conversely, the marked increase in proliferation induced by the loss of TET2 could be rescued exclusively by re-expression of wild-type or catalytically inactive TET2. Our data indicate that in the absence of TET2, mast cell differentiation is under the control of compensatory mechanisms mediated by other TET family members, while proliferation is strictly dependent on TET2 expression.
2016-05-04 | GSE79090 | GEO
Project description:Dioxygenases of the TET family impact genome functions by converting 5-methylcytosine in DNA to 5-hydroxymethylcytosine (5hmC), but their contribution to differentiation and function of immune cells is still incompletely understood. Here, we identified TET2 as a crucial regulator of mast cell differentiation and proliferation. Specifically, mast cell differentiation was impaired in absence of TET2, a defect that could be however compensated or further exacerbated modulating the activity of other TET family members. Mechanistically, delayed mast cell differentiation was related to the dysregulated expression of C/EBP transcription factors. Vice versa, the marked increase in proliferation induced by the absence of TET2 could be rescued exclusively by the specific re-expression of TET2 itself, regardless of its enzymatic activity. Our data indicate that in absence of TET2, mast cell differentiation is largely under the control of compensatory mechanisms mediated by other TET family members, while proliferation is strictly dependent on TET2 expression.
2016-05-04 | GSE77844 | 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 TET proteins TET1, TET2 and TET3 constitute a new family of dioxygenases that utilize molecular oxygen and the cofactors Fe(II) and 2-oxoglutarate to convert 5-methylcytosine (5mC) to 5-hydroxy-methylcytosine (5hmC) and further oxidation products in DNA1-5. Here we show that Tet1 and Tet2 have distinct roles in regulating 5hmC deposition and gene expression in mouse embryonic stem cells (mESC). Tet1 depletion in mESC primarily diminishes 5hmC levels at transcription start sites (TSS), whereas Tet2 depletion is mostly associated with decreased 5hmC in gene bodies relative to TSS. 5hmC is enriched at exon start and end sites, especially in exons that are highly expressed, and is significantly decreased upon Tet2 knockdown at the boundaries of high-expressed exons that are selectively regulated by Tet2. In differentiating murine B cells, Tet2 deficiency is associated with selective exon exclusion in the gene encoding the transmembrane phosphatase CD45. Tet2 depletion is associated with increased 5hmC and decreased 5mC at promoters/ TSS regions, possibly because of the redundant activity of Tet1. Together, these data indicate a complex interplay between Tet1 and Tet2 in mESC, and show that loss-of-function of a single TET protein does not necessarily lead to loss of 5hmC and a corresponding gain of 5mC, as generally assumed. The relation between Tet2 loss-of-function and selective changes in exon expression could potentially explain the frequent occurrence of both TET2 loss-of-function mutations and mutations in proteins involved in pre-mRNA splicing in myeloid malignancies in humans. Gene and exon expression analysis in mESC, Tet1 knockdown mESC, and Tet2 knockdown mESC by RNA-sequencing. Mapping of 5-hydroxymethylcytosine in mESC, Tet1 knockdown mESC, and Tet2 knockdown mESC by anti-CMS-seq. Mapping of methylcytosine in mESC, and Tet2 kd mESC by MeDIP-seq.
2014-01-16 | E-GEOD-50200 | biostudies-arrayexpress
Project description:The TET proteins TET1, TET2 and TET3 constitute a new family of dioxygenases that utilize molecular oxygen and the cofactors Fe(II) and 2-oxoglutarate to convert 5-methylcytosine (5mC) to 5-hydroxy-methylcytosine (5hmC) and further oxidation products in DNA1-5. Here we show that Tet1 and Tet2 have distinct roles in regulating 5hmC deposition and gene expression in mouse embryonic stem cells (mESC). Tet1 depletion in mESC primarily diminishes 5hmC levels at transcription start sites (TSS), whereas Tet2 depletion is mostly associated with decreased 5hmC in gene bodies relative to TSS. 5hmC is enriched at exon start and end sites, especially in exons that are highly expressed, and is significantly decreased upon Tet2 knockdown at the boundaries of high-expressed exons that are selectively regulated by Tet2. In differentiating murine B cells, Tet2 deficiency is associated with selective exon exclusion in the gene encoding the transmembrane phosphatase CD45. Tet2 depletion is associated with increased 5hmC and decreased 5mC at promoters/ TSS regions, possibly because of the redundant activity of Tet1. Together, these data indicate a complex interplay between Tet1 and Tet2 in mESC, and show that loss-of-function of a single TET protein does not necessarily lead to loss of 5hmC and a corresponding gain of 5mC, as generally assumed. The relation between Tet2 loss-of-function and selective changes in exon expression could potentially explain the frequent occurrence of both TET2 loss-of-function mutations and mutations in proteins involved in pre-mRNA splicing in myeloid malignancies in humans. Gene and exon expression analysis in mESC, Tet1 knockdown mESC, and Tet2 knockdown mESC by RNA-sequencing. Mapping of 5-hydroxymethylcytosine in mESC, Tet1 knockdown mESC, and Tet2 knockdown mESC by anti-CMS-seq. Mapping of methylcytosine in mESC, and Tet2 kd mESC by MeDIP-seq.
2014-01-16 | E-GEOD-50198 | biostudies-arrayexpress
Project description:The TET proteins TET1, TET2 and TET3 constitute a new family of dioxygenases that utilize molecular oxygen and the cofactors Fe(II) and 2-oxoglutarate to convert 5-methylcytosine (5mC) to 5-hydroxy-methylcytosine (5hmC) and further oxidation products in DNA1-5. Here we show that Tet1 and Tet2 have distinct roles in regulating 5hmC deposition and gene expression in mouse embryonic stem cells (mESC). Tet1 depletion in mESC primarily diminishes 5hmC levels at transcription start sites (TSS), whereas Tet2 depletion is mostly associated with decreased 5hmC in gene bodies relative to TSS. 5hmC is enriched at exon start and end sites, especially in exons that are highly expressed, and is significantly decreased upon Tet2 knockdown at the boundaries of high-expressed exons that are selectively regulated by Tet2. In differentiating murine B cells, Tet2 deficiency is associated with selective exon exclusion in the gene encoding the transmembrane phosphatase CD45. Tet2 depletion is associated with increased 5hmC and decreased 5mC at promoters/ TSS regions, possibly because of the redundant activity of Tet1. Together, these data indicate a complex interplay between Tet1 and Tet2 in mESC, and show that loss-of-function of a single TET protein does not necessarily lead to loss of 5hmC and a corresponding gain of 5mC, as generally assumed. The relation between Tet2 loss-of-function and selective changes in exon expression could potentially explain the frequent occurrence of both TET2 loss-of-function mutations and mutations in proteins involved in pre-mRNA splicing in myeloid malignancies in humans. Gene and exon expression analysis in mESC, Tet1 knockdown mESC, and Tet2 knockdown mESC by RNA-sequencing. Mapping of 5-hydroxymethylcytosine in mESC, Tet1 knockdown mESC, and Tet2 knockdown mESC by anti-CMS-seq. Mapping of methylcytosine in mESC, and Tet2 kd mESC by MeDIP-seq.
2014-12-03 | E-GEOD-63771 | biostudies-arrayexpress
Project description:DNA methylation plays critical roles in regulating muscle cell fate determination and myogenesis. Tet dioxygenases are responsible for active DNA demethylation. The functions of Tet proteins in muscle regeneration have not been well characterized. Here we find that Tet2 is required for complete regeneration after muscle injury. Loss of Tet2 in myoblasts leads to reduced fusion index and thinner myofibers. Tet2 activates transcription of key differentiation modulator Myogenin (MyoG) further promoting myoblast differentiation and fusion. Re-expressing of MyoG in Tet2 KO myoblasts rescues the differentiation and fusion defects. Further mechanistic analysis reveals that Tet2 facilitates the recruitment of H3K4me1 and H3K27ac, increases the chromatin accessibility, and MyoD binding on MyoG enhancer. These functions are specifically executed by Tet2, but not Tet1 and Tet3. We identified the Tet2 specific function during myogenesis and shed new lights on DNA methylation and pioneer transcription factor transcription activation.
2021-06-01 | GSE158648 | GEO
Project description:DNA methylation plays critical roles in regulating muscle cell fate determination and myogenesis. Tet dioxygenases are responsible for active DNA demethylation. The functions of Tet proteins in muscle regeneration have not been well characterized. Here we find that Tet2 is required for complete regeneration after muscle injury. Loss of Tet2 in myoblasts leads to reduced fusion index and thinner myofibers. Tet2 activates transcription of key differentiation modulator Myogenin (MyoG) further promoting myoblast differentiation and fusion. Re-expressing of MyoG in Tet2 KO myoblasts rescues the differentiation and fusion defects. Further mechanistic analysis reveals that Tet2 facilitates the recruitment of H3K4me1 and H3K27ac, increases the chromatin accessibility, and MyoD binding on MyoG enhancer. These functions are specifically executed by Tet2, but not Tet1 and Tet3. We identified the Tet2 specific function during myogenesis and shed new lights on DNA methylation and pioneer transcription factor transcription activation.
2021-06-01 | GSE158647 | GEO
Project description:DNA methylation plays critical roles in regulating muscle cell fate determination and myogenesis. Tet dioxygenases are responsible for active DNA demethylation. The functions of Tet proteins in muscle regeneration have not been well characterized. Here we find that Tet2 is required for complete regeneration after muscle injury. Loss of Tet2 in myoblasts leads to reduced fusion index and thinner myofibers. Tet2 activates transcription of key differentiation modulator Myogenin (MyoG) further promoting myoblast differentiation and fusion. Re-expressing of MyoG in Tet2 KO myoblasts rescues the differentiation and fusion defects. Further mechanistic analysis reveals that Tet2 facilitates the recruitment of H3K4me1 and H3K27ac, increases the chromatin accessibility, and MyoD binding on MyoG enhancer. These functions are specifically executed by Tet2, but not Tet1 and Tet3. We identified the Tet2 specific function during myogenesis and shed new lights on DNA methylation and pioneer transcription factor transcription activation.
2021-06-01 | GSE158646 | GEO