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Tet2 regulates Sin3a recruitment at active enhancers in embryonic stem cells

ABSTRACT: In this study: (1) we distinguished Tet2 target genes that are regulated by its catalytic vs. noncatalytic functions in ESCs by transcriptomic profiling of Tet2 wildtype (WT), Tet2 catalytic mutant (Mut), and Tet2 knockout (KO) mouse ESCs by RNA-seq. (2) We mapped genome-wide DNA methylation of Tet2-WT, Tet2-Mut, and Tet2-KO ESCs by WGBS, to establish a critical role for Tet2 in demethylating promoters and enhancers of its catalytic target genes. (3) We determined how the genome-wide occupancy of the epigenetic modifiers Sin3a and Sap30 and the enrichment of H3K27ac, are affected in Tet2-Mut and Tet2-KO ESCs versus Tet2-WT by CUT&Tag and identified that Tet2 deficiency diminishes Sin3a occupancy at promoters and enhancers. (4) We mapped Sin3a levels genome-wide in Tet1/2 double catalytic mutant (DMUT) and Tet1/2 double knockout (DKO) ESCs, and found that deficiency of both Tet1 and Tet2 resulted in decreased levels of Sin3a in a subset of active enhancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE213398 | GEO | 2023/06/23

REPOSITORIES: GEO

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Tet1 regulates embryonic stem cell differentiation programs and development independent of its catalytic activity.

Project description:In this study: (1) we characterized the Tet1 non-catalytic functions in the regulation of ESC gene expression programs by performing transcriptomic analysis of Tet1 wild type (WT), Tet1 catalytic mutant (Mut) and Tet1 knockout (KO) mouse ESCs by RNA-seq to identify differentially expressed genes. (2) We mapped the genome-wide occupancy of endogenously FLAG-tagged Tet1-WT and Tet1-Mut in ESCs by CUT&Tag using a specific antibody against FLAG. (3) We determined how the genome-wide occupancy of the epigenetic modifiers: Ezh2, Sin3a, Chd4 and the enrichment of histone marks: H3K27me3, H3K4me3 and H3K27ac, are affected in Tet1-KO ESCs versus Tet1-WT and Tet1-Mut by CUT&Tag or CUT&RUN. (4) We analyzed methylation levels and distribution in Tet1-WT, Tet1-Mut and Tet1-KO ESCs by WGBS, to confirm Tet1 non-catalytic targets with no differential methylation. (5) We explored whether Tet1 non-catalytic functions play a role in chromatin accessibility by performing ATAC-seq in Tet1-WT, Tet1-Mut and Tet1-KO ESCs.

2022-01-25 | GSE176389 | GEO

Amplicon bisulfite sequencing of LINE-1 elements in TET catalytic mutants and DPPA3 KO ESCs rescued by doxycylin induced overexpression

Project description:Tet1, Tet2 and Tet1/Tet2 catalytic mutants as well as DPPA3 KO ESCs harboring a doxycyclin inducible Dppa3 transgene were induced for several days to monitor LINE-1 methylation levels.

2020-10-23 | E-MTAB-9654 | biostudies-arrayexpress

Comparative analysis of Tet2 catalytic deficient and knockout bone marrow over time

Project description:In this study, we investigated the role of Tet2 in regulation of hematopoietic genes by performing transcriptomic analysis of Tet2 WT, Mut, and KO LSK and Lin– cells at 3, 6, 9, and 12 months by RNA-seq, and mapping the DNA methylation landscape of 3-month-old Tet2 WT, Mut, and KO LSK and Lin– cells. (1) We find that loss of Tet2 (Tet2 KO) vs. a loss of Tet2 catalytic function (Tet2 Mut) at different time points and cell types causes distinct gene expression changes when compared to WT samples as assessed by RNA-seq. (2) Additionally, we find that many genes implicated in lymphoma and leukemia are deregulated in Tet2 Mut and KO LSK and Lin– cells, consistent with the phenotypes observed in mice transplanted with Tet2 Mut and KO bone marrow. (3) We also mapped genome-wide DNA methylation levels of WT, Tet2 Mut, and KO LSK and Lin– cells at 3 months by WGBS and establish a role for Tet2 in demethylating genes implicated in lymphoma and leukemia initiation and progression.

2023-06-01 | GSE227977 | GEO

Catalytic dependent and independent roles of Tet3 in activation of ectodermal and silencing of mesodermal programs during neuroectoderm specification

Project description:In this study: (1) we distinguished Tet3 target genes that are regulated by its catalytic vs. noncatalytic functions in neuroectoderm (NE) cells by transcriptomic profiling of Tet3 wildtype (WT), Tet3 catalytic mutant (Mut), and Tet3 knockout (KO) NE cells by RNA-seq. (2) We mapped genome-wide DNA methylation of Tet3-WT, Tet3-Mut, and Tet3-KO NE cells by WGBS. (3) We determined Tet3 genome-wide occupancy in Tet3-WT NE cells by CUT&Tag. (4) We mapped 5hmC rich regions in Tet3-WT, Tet3-Mut, and Tet3-KO NE cells by hmeDIP. (5) We overexpressed (OE) the Tet3 target gene Dnmt1 (D) or an empty vector (EV) in Tet3-WT, Tet3-Mut, and Tet3-KO NE cells and assessed gene expression by RNA-seq. (6) We overexpressed (OE) Tet3 (T) or an empty vector (EV) in Tet3-WT, Tet3-Mut, and Tet3-KO NE cells and examined gene expression changes in these cells by RNA-seq.

2024-04-02 | GSE237800 | GEO

TETs controls maintenance DNA methylation via the regulation of Dppa3

Project description:Dissection of catalytic and non-catalytic functions of Tet1 and Tet2. Transcriptome profiling of wild type, Tet1 catalytic mutants, Tet2 and Tet1/2 catalytic mutant catalytic during EpiLC differentiation.

2020-10-05 | E-MTAB-6797 | biostudies-arrayexpress

Non-catalytic functions of Tet2 are essential to regulate hematopoietic stem and progenitor cell homeostasis

Project description:To identify genes that are influenced by the catalytic and non-catalytic functions of Tet2 in hematopoietic stem and progenitor cells (HSPCs), we analyzed the gene expression profiles of Tet2 catalytic mutant (Tet2 Mut), Tet2 knockout (Tet2 KO) and wild-type HSPCs (or LSK, Lin–Sca-1+c-Kit+) and multi-potent progenitor (or MPP, Lin–) cells by RNA-seq.

2019-08-05 | GSE132090 | GEO

TET1 interactome by SILAC IP-MS in mouse ESCs

Project description:TET1 maintains hypomethylation at bivalent promoters through its catalytic activity in embryonic stem cells (ESCs). However, whether and how TET1 exerts catalytic activity-independent functions in regulating bivalent genes is not well understood. Therefore, we mapped the TET1 interactome in mouse ESCs using a SILAC IP-MS proteomics approach.

2022-06-10 | PXD033587 | Pride

Dissection of TET1 catalytic and non-catalytic functions reveals DNA demethylation independent gene and ERV regulation

Project description:Surveillance of DNA methylation in mammals is critical for genome stability and epigenetic regulation. The discovery of the ten-eleven translocation (TET) proteins catalyzing the oxidation from 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) revolutionized the understanding of DNA methylation dynamics. Interestingly, in recent years evidence accumulated that TET1 also harbours non-catalytic functions. However, the role and mechanism of TET1 DNA demethylation independent functions still remain poorly understood. Here, we use genome engineering and quantitative multi-omics approaches to dissect the non-catalytic role of TET1. Strikingly, we find that the majority of transcriptional regulation depends on non-catalytic functions of TET1. To gain insights into possible mechanisms by which TET1 regulates transcription independent of DNA demethylation, we asked if the loss of TET1 is accompanied by changes in the histone modificaiton landscape. To this end, we compared the relative abundances of core histone modifications between Tet1 KO, Tet1 CM and WT mESCs using quantitative LC-MS/MS analysis. Surprisingly, we observed a profound global reduction of pH4Kac and H4K20me3 as well as H3K27me3 in Tet1 KO mESC. Vice versa, the monomethylation states of the latter two residues, H3K27me1 and H4K20me1 were significantly increased in Tet1 KO. Similar to the results from the transcriptome data, most of these changes were specific to Tet1 KO cells.

2022-08-11 | PXD028566 | Pride

Combined deficiency of Tet1 and Tet2 is compatible with development but leads to epigenetic instability

Project description:Tet enzymes (Tet1/2/3) convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Tet1 and Tet2 mediate 5hmC generation in mouse embryonic stem cells (ESCs) and various embryonic and adult tissues. To investigate the effects of combined deficiency of Tet1 and Tet2 on pluripotency and development, we have generated Tet1 and Tet2 double knockout (DKO) ESCs and mice. DKO ESCs were depleted of 5hmC, but remained pluripotent with subtle defects in differentiation and changes in gene expression. Double mutant embryos and chimeras exhibited mid-gestation defects and postnatal DKO mice displayed partially penetrant neonatal lethality and stochastic perturbation of imprinting. Viable DKO animals developed normally to adulthood but had reduced 5hmC level, increased 5mC level and lacked 5hmC in germ cells. Nevertheless, DKO mice of both sexes were fertile with females having smaller ovaries and reduced fertility. Our data suggest that both Tet1 and Tet2 contribute to 5hmC levels during development. Their combined loss does not block differentiation and embryogenesis, but leads to partially penetrant embryonic and perinatal abnormalities and compromised viability. Moreover, the presence of substantial levels of 5hmC in DKO embryos and adult mice suggests a significant contribution of Tet3 in hydroxylation of 5mC during development. Methylation patterns in tissue samples from a series of wt and Tet1/Tet2 DKO embryos, neonates and adults were generated using methylated DNA immunoprecipitation with antibodies against 5mC (MeDIP) and 5hmC (hMeDIP) followed by deep sequencing.

2013-02-01 | E-GEOD-42396 | biostudies-arrayexpress

Gene expression profiles of Tet1 knockout (T1KO), Tet2 knockout (T2KO) and Tet1/Tet2 double knockout (DKO) mouse embryonic stem cells.

Project description:Global gene expression profile of single and double mutant mouse ES cells were compared to wt ES cells. Two male Tet1 KO, one male Tet2 KO, two male double KO, two female double KO, two male WT and two female WT mouse ES cells were compared.

2013-02-01 | GSE42991 | GEO

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