Similar Datasets
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: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: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:TET2 and TET3 loss disrupts small intestine differentiation and homeostasis
| PRJNA823706 | ENA
Project description:TET2 and TET3 loss disrupts small intestine differentiation and homeostasis [scRNA-seq]
| PRJNA823709 | 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 [Bisulfite-seq]
| PRJNA823711 | ENA
Project description:Although much research has been done on the diversity of the gut microbiome, little is known about how it influences intestinal homeostasis under normal and pathogenic conditions. Epigenetic mechanisms have recently been suggested to operate at the interface between the microbiota and the intestinal epithelium. We performed whole-genome bisulfite sequencing on conventionally raised and germ-free mice, and discovered that exposure to commensal microbiota induced localized DNA methylation changes at regulatory elements, which are TET2/3-dependent. This culminated in the activation of a set of ‘early sentinel’ response genes to maintain intestinal homeostasis. Furthermore, we demonstrated that exposure to the microbiota in dextran sodium sulfate-induced acute inflammation results in profound DNA methylation and chromatin accessibility changes at regulatory elements, leading to alterations in gene expression programs enriched in colitis- and colon-cancer-associated functions. Finally, by employing genetic interventions, we show that microbiota-induced epigenetic programming is necessary for proper intestinal homeostasis in vivo.
2022-06-16 | GSE206169 | GEO
Project description:TET enzymes oxidize 5-methylcytosine to 5-hydroxymethylcytosine and other oxidized methylcytosines in DNA. Here we examine the role of TET proteins in regulatory T (Treg) cells. Tet2/3fl/flFoxp3Cre mice lacking Tet2 and Tet3 in Treg cells develop inflammatory disease, and Treg cells from these mice show altered expression of Treg signature genes and upregulation of genes involved in cell cycle, DNA damage and cancer. In littermate mice with severe inflammation, both CD4+Foxp3+ and CD4+Foxp3- cells show strong skewing towards Tfh/Th17 phenotypes. Wild-type Treg cells in mixed bone marrow chimeras and in Tet2/3fl/flFoxp3WT/Cre heterozygous female mice are unable to rescue the aberrant properties of Tet2/3fl/flFoxp3Cre Treg cells. Treg cells from Tet2/3fl/flFoxp3Cre mice tend to lose Foxp3 expression, and transfer of total CD4+ T cells isolated from Tet2/3fl/flFoxp3Cre mice could elicit inflammatory disease in fully immunocompetent mice. Together, these data indicate that Tet2 and Tet3 are guardians of Treg cell stability and immune homeostasis.
| S-EPMC6494907 | biostudies-other