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Combined loss of Tet1 and Tet2 promotes B-cell, but not myeloid malignancies in mice

ABSTRACT: TET1/2/3 are methylcytosine dioxygenases regulating cytosine hydroxymethylation in the genome. Tet1 and Tet2 are abundantly expressed in HSC/HPCs and implicated in the pathogenesis of hematological malignancies. Tet2-deletion in mice causes myeloid malignancies, while Tet1-null mice develop B-cell lymphoma after an extended period of latency. Interestingly, TET1 and TET2 were often concomitantly down-regulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/Tet2 in HSC maintenance and development of hematological malignancies using Tet1/2 double knockout (DKO) mice. DKO and Tet2-/- HSC/HPCs had overlapping and unique 5hmC and 5mC profiles and behaved differently. DKO mice exhibited strikingly decreased incidence and delayed onset of myeloid malignancies compared to Tet2-/- mice and in contrast developed lethal B-cell malignancies. Transcriptome analysis of DKO tumors revealed expression changes in many genes dysregulated in human B-cell malignancies, such as LMO2, BCL6 and MYC. These results highlight the critical roles of TET1 or TET2 individually and their cross-talks in the pathogenesis of hematological malignancies. Given the role of Tet proteins in 5mC oxidation, we employed a previously established chemical labeling and affinity purification method coupled with high-throughput sequencing (hMe-Seal) to profile the genome-wide distribution of 5hmC, as well as methylated DNA immunoprecipitation (MeDIP) coupled with high-throughput sequencing (MeDIP-seq) to profile 5mC using BM LK cells purified from young WT, Tet2-/- and DKO mice (6-10 wks old).

ORGANISM(S): Mus musculus

SUBMITTER: Peng Jin

PROVIDER: E-GEOD-73611 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Combined loss of Tet1 and Tet2 promotes B-cell, but not myeloid malignancies in mice

Project description:TET1/2/3 are methylcytosine dioxygenases regulating cytosine hydroxymethylation in the genome. Tet1 and Tet2 are abundantly expressed in HSC/HPCs and implicated in the pathogenesis of hematological malignancies. Tet2-deletion in mice causes myeloid malignancies, while Tet1-null mice develop B-cell lymphoma after an extended period of latency. Interestingly, TET1 and TET2 were often concomitantly down-regulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/Tet2 in HSC maintenance and development of hematological malignancies using Tet1/2 double knockout (DKO) mice. DKO and Tet2-/- HSC/HPCs had overlapping and unique 5hmC and 5mC profiles and behaved differently. DKO mice exhibited strikingly decreased incidence and delayed onset of myeloid malignancies compared to Tet2-/- mice and in contrast developed lethal B-cell malignancies. Transcriptome analysis of DKO tumors revealed expression changes in many genes dysregulated in human B-cell malignancies, such as LMO2, BCL6 and MYC. These results highlight the critical roles of TET1 or TET2 individually and their cross-talks in the pathogenesis of hematological malignancies.

2015-11-12 | GSE73611 | GEO

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

Genome-wide single base resolution profiling of 5-methyl and 5-hydroxymethylcytosine in glioblastoma

Project description:Through parallel processing of genomic DNA with bisulfite and oxidative bisulfite treatments on Illumina 450K arrays we resolved both 5mC and 5hmC in glioblastoma tissues. We developed and applied a novel technique for estimating 5mC, 5hmC, and unmethylated proportions from array data to glioblastoma tissues and compare with normal brain tissue. Genomic distribution of 5hmC was associated with features of transcription despite the glioblastoma genome being relatively depleted of 5hmC. When integrating 5mC and 5hmC data using a Gaussian finite mixture model approach, we observed significant associations between 5hmC levels and gene-sets involved in immune and RNA regulatory processes. We also observed an enrichment of 5hmC in introns, enhancer regions, and genes that are actively transcribed in glioblastomas from TCGA. Significant differences in patient survival were observed among classes of 5hmC obtained from a recursively partitioned mixture model. Glioblastoma dervied (n=30) DNA was subjected to tandem bisulfite and oxidative bisulfite conversion with an input of 4ug per sample using the TrueMethylÂ® kit v.1.1 (Cambridge Epigenetix) protocol optimized for Illumina HumanMethylation450 arrays.

2016-08-22 | E-GEOD-73895 | biostudies-arrayexpress

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

2013-02-01 | GSE42396 | GEO

Distinct roles of Tet1 and Tet2 in mouse embryonic stem cells (CMS-Seq)

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

Distinct roles of Tet1 and Tet2 in mouse embryonic stem cells (RNA-Seq)

2014-01-16 | E-GEOD-50198 | biostudies-arrayexpress

Distinct roles of Tet1 and Tet2 in mouse embryonic stem cells [MeDIP-Seq]

2014-12-03 | E-GEOD-63771 | biostudies-arrayexpress

Application of a low cost array-based technique - TAB-Array - for quantifying and mapping both 5mC and 5hmC at single base resolution.

Project description:5-hydroxymethylcytosine (5hmC), an oxidized derivative of 5-methylcytosine (5mC), has been implicated as an important epigenetic regulator of mammalian development. Current procedures use cost-prohibitive DNA sequencing methods to discriminate 5hmC from 5mC, limiting their accessibility to the scientific community. Here we report a method that combines TET-assisted bisulfite conversion with Illumina 450K DNA methylation arrays for a low-cost high-throughput approach that distinguishes 5hmC and 5mC signals. Implementing this approach, termed TAB-array, we assessed DNA methylation dynamics in the differentiation of human pluripotent stem cells into cardiovascular and neural progenitors. With the ability to discriminate 5mC and 5hmC, we found a much larger number of dynamically methylated genomic regions implicated in the development of these lineages than we could detect by 5mC analysis alone. The increased resolution and accuracy afforded by this approach provides a powerful means to investigate the distinct contributions of 5mC and 5hmC in human development and disease. We generated illumina 450k DNA methylation data for a total of 9 sample groups with two biological replicates for each group. Data for 4/9 groups were generated from glucosylated and bisulfite converted DNA, from human induced plurupotent stem cells (hIPSCs), differentiated cardiovascular progenitors (CVPs), differentiated neural progenitors (NPCs), and fibroblasts. Data for the next 4/9 groups were generated from glucosylated, TET-oxidized and bisulfite converted DNA, from and included replicates of hIPSCs, CVPs, NPCs, and fibroblasts. Data for the last group was generated from standard bisulfite converted DNA (not glucosylated) from fibroblasts.

2014-12-12 | E-GEOD-60225 | biostudies-arrayexpress

Tet1 and Tet2 mediate epigenetic regulation of developmental genes by protecting DNA methylation canyons against hypermethylation [Bisulfite-Seq]

Project description:This study uses whole methylome sequencing to characterize the methylomes of mouse embryonic fibroblasts (MEF's). Two conditions were analyzed, MEF cells with intact TET1/TET2 enzymes (WT) and MEF cells with TET1/TET2 knocked out (DKO). Our results identify sets of differentially methylated genes which are correlated with TET1/TET2 induced expression changes of the corresponding genes. Whole methylome analysis of M. musculus MEF cells. Two conditions were sequenced and analyzed, the first is wild type (WT), the second (DKO) corresponds to knock-out of TET1 and TET2 enzymes.

2015-12-07 | E-GEOD-58610 | biostudies-arrayexpress

Loss of 5-hydroxymethylcytosine is linked to gene body hypermethylation in kidney cancer

Project description:Aberrant DNA methylation is common in cancer. To associate DNA methylation with gene function, we performed RNAseq upon tumor tissue and matched normal tissues of two ccRCC (clear cell renal cell carcinoma) patients. To quantify 5mC and 5hmC level in each CG site at genome-wide level, we performed BS-seq and TAB-seq upon tumor tissue and matched normal tissues of two ccRCC (clear cell renal cell carcinoma) patients, respectively. mRNA profiles of tumor and matched normal tissues from two ccRCC patients were generated by deep sequencing, using Hiseq 2000. Single-nucleotide-resolution, whole-genome, 5mC and 5hmC profiles of tumor and matched normal tissues from two ccRCC (clear cell renal cell carcinoma) patients were generated by deep sequencing, using Hiseq 2000.

2016-02-29 | E-GEOD-63183 | biostudies-arrayexpress

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