TET2 and TET3 loss disrupts small intestine differentiation and homeostasis [Bisulfite-seq]
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PROVIDER: PRJNA823711 | ENA |
REPOSITORIES: ENA
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Project description:TET2 and TET3 loss disrupts small intestine differentiation and homeostasis
| PRJNA823706 | ENA
Project description:TET2 and TET3 loss disrupts small intestine differentiation and homeostasis [RNA-seq]
| PRJNA823710 | ENA
Project description:TET2 and TET3 loss disrupts small intestine differentiation and homeostasis [scRNA-seq]
| PRJNA823709 | ENA
Project description:The Ten-eleven translocation (TET) DNA demethylases play a well-known role in epigenetic regulation and mouse development. However, their function in cellular differentiation and tissue homeostasis remains poorly understood . Since previous results have implied Tet2/3 in mouse intestinal inflammation, we ablated both enzymes in intestinal epithelial cells (IECs). Our results show that the corresponding mice developed a novel phenotype displaying a severe homeostasis imbalance and a blockage in differentiation trajectories. Transcriptomic, single-cell RNA sequencing (scRNA-seq), single-molecule fluorescence in situ hybridization (sm-FISH), and immunohistochemical analyses revealed that the Tet2/3-deleted mice show a massive loss of mature Paneth cells concomitant with fewer Tuft and more enteroendocrine cells. Further results showed major changes in DNA methylation at putative enhancers, which were associated with cell fate-determining transcription factors and functional effector genes. Notably, pharmacological inhibition of DNA methylation partially rescued the methylation and cellular phenotypes. Moreover, the loss of Tet2/3 results in an altered microbiome, presumably increasing gut susceptibility to inflammatory signals (Ansari et al., 2020). Together, our results uncovered previously unrecognized critical roles for DNA demethylation in intestinal development and function, culminating in the establishment of normal intestinal crypts in mice.
2023-05-22 | GSE200227 | GEO
Project description:TET2/3 play a well-known role in epigenetic regulation and mouse development. However, their function in cellular differentiation and tissue homeostasis remains poorly understood. Here we show that ablation of TET2/3 in intestinal epithelial cells results in a murine phenotype characterized by a severe homeostasis imbalance in the small intestine. Tet2/3-deleted mice show a pronounced loss of mature Paneth cells as well as fewer Tuft and more Enteroendocrine cells. Further results show major changes in DNA methylation at putative enhancers, which are associated with cell fate-determining transcription factors and functional effector genes. Notably, pharmacological inhibition of DNA methylation partially rescues the methylation and cellular defects. TET2/3 loss also alters the microbiome, predisposing the intestine to inflammation under homeostatic conditions and acute inflammation-induced death. Together, our results uncover previously unrecognized critical roles for DNA demethylation, possibly occurring subsequently to chromatin opening during intestinal development, culminating in the establishment of normal intestinal crypts.
| S-EPMC10326054 | biostudies-literature
Project description:Nephron endowment is a key determinant of later life hypertension and kidney disease. Here we studied whether epigenetic changes, specifically the ten–eleven translocation (Tet) DNA demethylase family, Tet1, Tet2, and Tet3-mediated active DNA hydroxymethylation is necessary for gene expression regulation and kidney differentiation. We generated mice with deletion of Tet1, Tet2 or Tet3 in Six2 positive nephron progenitors (NP). We did not observe changes in development or kidney function in mice with nephron progenitor-specific deletion of Tet1, Tet2, Tet3 or Tet1/Tet2 or Tet1/Tet3. On the other hand, mice with combined Tet2 and Tet3 loss in Six2-positive NPCs failed to form nephrons leading to kidney failure and perinatal death. Tet2 and Tet3 loss in Six2-positive NPs resulted in defect in mesenchymal to epithelial transition and renal vesicle differentiation. Whole genome bisulfite sequencing, single cell RNA sequencing, and gene and protein expression assay identified a defect in expression in genes in the WNT-β-catenin signaling pathway in absence of Tet2 and Tet3 due to a failure in demethylation of these loci. Our results indicate the key role of Tet2 and Tet3-mediated active cytosine hydroxymethylation in NPs in kidney development and nephron endowment.
2022-11-23 | GSE212715 | GEO
Project description:TET proteins convert 5-methylcytosine to 5-hydroxymethylcytosine, an emerging dynamic epigenetic state of DNA that can influence transcription. Evidence has linked TET1 function to epigenetic repression complexes, yet mechanistic information, especially for the TET2 and TET3 proteins, remains limited. Here, we show a direct interaction of TET2 and TET3 with O-GlcNAc transferase (OGT). OGT does not appear to influence hmC activity, rather TET2 and TET3 promote OGT activity. TET2/3-OGT co-localize on chromatin at active promoters enriched for H3K4me3 and reduction of either TET2/3 or OGT activity results in a direct decrease in H3K4me3 and concomitant decreased transcription. Further, we show that Host Cell Factor 1 (HCF1), a component of the H3K4 methyltransferase SET1/COMPASS complex, is a specific GlcNAcylation target of TET2/3-OGT, and modification of HCF1 is important for the integrity of SET1/COMPASS. Additionally, we find both TET proteins and OGT activity promote binding of the SET1/COMPASS H3K4 methyltransferase, SETD1A, to chromatin. Finally, studies in Tet2 knockout mouse bone marrow tissue extend and support the data as decreases are observed of global GlcNAcylation and also of H3K4me3, notably at several key regulators of haematopoiesis. Together, our results unveil a step-wise model, involving TET-OGT interactions, promotion of GlcNAcylation, and influence on H3K4me3 via SET1/COMPASS, highlighting a novel means by which TETs may induce transcriptional activation. ChIP-Seq experiments were performed on Illumina HiScanSQ sequencer in wild-type HEK293T cells for H3K4me3 histone marks, O-GlcNAc and HCF1, for HT-TET2, HT-TET3 and HT-OGT in HEK293T cells overexpressing those three fusion proteins and in TET2 Kd HEK293T cells for H3K4me3 histone marks. ChIP-Seqs were also performed in mouse bone marrow tissues for H3K4me3 histone marks, O-GlcNAc, endogenous Tet2 and in Tet2 Ko bone marrow tissues for H3K4me3 histone marks.
2013-02-07 | E-GEOD-36620 | biostudies-arrayexpress
Project description:The Ten-eleven translocation (TET) DNA demethylases play a well-known role in epigenetic regulation and mouse development. However, their function in cellular differentiation and tissue homeostasis remains poorly understood . Since previous results have implied Tet2/3 in mouse intestinal inflammation, we ablated both enzymes in intestinal epithelial cells (IECs). Our results show that the corresponding mice developed a novel phenotype displaying a severe homeostasis imbalance and a blockage in differentiation trajectories. Transcriptomic, single-cell RNA sequencing (scRNA-seq), single-molecule fluorescence in situ hybridization (sm-FISH), and immunohistochemical analyses revealed that the Tet2/3-deleted mice show a massive loss of mature Paneth cells concomitant with fewer Tuft and more enteroendocrine cells. Further results showed major changes in DNA methylation at putative enhancers, which were associated with cell fate-determining transcription factors and functional effector genes. Notably, pharmacological inhibition of DNA methylation partially rescued the methylation and cellular phenotypes. Moreover, the loss of Tet2/3 results in an altered microbiome, presumably increasing gut susceptibility to inflammatory signals (Ansari et al., 2020). Together, our results uncovered previously unrecognized critical roles for DNA demethylation in intestinal development and function, culminating in the establishment of normal intestinal crypts in mice.
2023-05-22 | GSE200229 | GEO
Project description:The Ten-eleven translocation (TET) DNA demethylases play a well-known role in epigenetic regulation and mouse development. However, their function in cellular differentiation and tissue homeostasis remains poorly understood . Since previous results have implied Tet2/3 in mouse intestinal inflammation, we ablated both enzymes in intestinal epithelial cells (IECs). Our results show that the corresponding mice developed a novel phenotype displaying a severe homeostasis imbalance and a blockage in differentiation trajectories. Transcriptomic, single-cell RNA sequencing (scRNA-seq), single-molecule fluorescence in situ hybridization (sm-FISH), and immunohistochemical analyses revealed that the Tet2/3-deleted mice show a massive loss of mature Paneth cells concomitant with fewer Tuft and more enteroendocrine cells. Further results showed major changes in DNA methylation at putative enhancers, which were associated with cell fate-determining transcription factors and functional effector genes. Notably, pharmacological inhibition of DNA methylation partially rescued the methylation and cellular phenotypes. Moreover, the loss of Tet2/3 results in an altered microbiome, presumably increasing gut susceptibility to inflammatory signals (Ansari et al., 2020). Together, our results uncovered previously unrecognized critical roles for DNA demethylation in intestinal development and function, culminating in the establishment of normal intestinal crypts in mice.
2023-05-22 | GSE200228 | GEO
Project description:We report the global gene expression in Tet2/Tet3-sufficient and -deficient B cell subsets. We found an alteration of multiple gene expressions in the absence of Tet2 and Tet3 in B cells. This study provides a basis for the comprehensive understanding of Tet function in B cells.
2020-07-08 | GSE137914 | GEO