Tet1 and Tet2 Protect DNA Methylation Canyons against Hypermethylation

Wiehle, Laura; Raddatz, Günter; Musch, Tanja; Dawlaty, Meelad M.; Jaenisch, Rudolf; Lyko, Frank; Breiling, Achim

doi:10.1128/mcb.00587-15

Cited by 55 publications

(48 citation statements)

References 46 publications

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“…TET family members can promote gene activation or repression (Pastor et al, 2013; Shen et al, 2014), and these transcriptional alterations are coupled to altered DNA methylation across gene bodies, enhancers, and at the boundaries of DNA methylation canyons (Rasmussen et al, 2015; Wiehle et al, 2015). To identify the locus-specific changes in DNA methylation upon Tet2 restoration, we performed single base resolution reduced representative bisulfite sequencing (RRBS) (Gu et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression

Cimmino

Dolgalev

Wang³

et al. 2017

Cell

527

523

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SUMMARY Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) and are associated with a DNA hypermethylation phenotype. To determine the role of TET2 deficiency in leukemia stem cell maintenance, we generated a reversible transgenic RNAi mouse to model restoration of endogenous Tet2 expression. Tet2 restoration reverses aberrant hematopoietic stem and progenitor cell (HSPC) self-renewal in vitro and in vivo. Treatment with vitamin C, a cofactor of Fe2+ and α-KG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs and suppresses human leukemic colony formation and leukemia progression of primary human leukemia PDXs. Vitamin C also drives DNA hypomethylation and expression of a TET2-dependent gene signature in human leukemia cell lines. Furthermore, TET-mediated DNA oxidation induced by vitamin C treatment in leukemia cells enhances their sensitivity to PARP inhibition and could provide a safe and effective combination strategy to selectively target TET deficiency in cancer.

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Section: Resultsmentioning

confidence: 99%

Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression

Cimmino

Dolgalev

Wang³

et al. 2017

Cell

527

523

View full text Add to dashboard Cite

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“…Loss of either of these proteins gives rise to aberrant promoter methylation and expression of developmental genes during cell differentiation. Similarly, hypermethylation of distinct gene regulatory regions was observed in mouse embryonic fibroblasts (MEFs) depleted for TET1-TET2 [107] or for TDG [31,57,108], the latter correlating well with sites of 5fC enrichment in TDG-deficient ESCs [109]. Overall, the data supporting a critical role of active DNA demethylation via the TET-TDG pathway in the control of cell differentiation and developmental processes is compelling.…”

Section: Control Of Pluripotency and Cellular Differentiationmentioning

confidence: 86%

Active DNA demethylation by DNA repair: Facts and uncertainties

2016

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Pathways that control and modulate DNA methylation patterning in mammalian cells were poorly understood for a long time, although their importance in establishing and maintaining cell type-specific gene expression was well recognized. The discovery of proteins capable of converting 5-methylcytosine (5mC) to putative substrates for DNA repair introduced a novel and exciting conceptual framework for the investigation and ultimate discovery of molecular mechanisms of DNA demethylation. Against the prevailing notion that DNA methylation is a static epigenetic mark, it turned out to be dynamic and distinct mechanisms appear to have evolved to effect global and locus-specific DNA demethylation. There is compelling evidence that DNA repair, in particular base excision repair, contributes significantly to the turnover of 5mC in cells. By actively demethylating DNA, DNA repair supports the developmental establishment as well as the maintenance of DNA methylation landscapes and gene expression patterns. Yet, while the biochemical pathways are relatively well-established and reviewed, the biological context, function and regulation of DNA repair-mediated active DNA demethylation remains uncertain. In this review, we will thus summarize and critically discuss the evidence that associates active DNA demethylation by DNA repair with specific functional contexts including the DNA methylation erasure in the early embryo, the control of pluripotency and cellular differentiation, the maintenance of cell identity, and the nuclear reprogramming.

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“…When Dnmt3a was deleted in mouse hematopoietic stem cells, DNA methylation canyons became eroded (Jeong et al ., 2014), causing reduced methylation variance and reduced spatial correlation of methylation marks at specific target loci. Similar observations were made in mouse embryonic fibroblasts that lack the Tet1 and Tet2 dioxygenases (Wiehle et al ., 2016). Interestingly, we also observed a significant relationship between age and the normalized gene expression level of TET1 , which becomes moderately, but significantly ( P < 0.05) reduced with age (Fig.…”

Section: Discussionmentioning

confidence: 99%

Reduced DNA methylation patterning and transcriptional connectivity define human skin aging

et al. 2016

Self Cite

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SummaryEpigenetic changes represent an attractive mechanism for understanding the phenotypic changes associated with human aging. Age‐related changes in DNA methylation at the genome scale have been termed ‘epigenetic drift’, but the defining features of this phenomenon remain to be established. Human epidermis represents an excellent model for understanding age‐related epigenetic changes because of its substantial cell‐type homogeneity and its well‐known age‐related phenotype. We have now generated and analyzed the currently largest set of human epidermis methylomes (N = 108) using array‐based profiling of 450 000 methylation marks in various age groups. Data analysis confirmed that age‐related methylation differences are locally restricted and characterized by relatively small effect sizes. Nevertheless, methylation data could be used to predict the chronological age of sample donors with high accuracy. We also identified discontinuous methylation changes as a novel feature of the aging methylome. Finally, our analysis uncovered an age‐related erosion of DNA methylation patterns that is characterized by a reduced dynamic range and increased heterogeneity of global methylation patterns. These changes in methylation variability were accompanied by a reduced connectivity of transcriptional networks. Our findings thus define the loss of epigenetic regulatory fidelity as a key feature of the aging epigenome.

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Tet1 and Tet2 Protect DNA Methylation Canyons against Hypermethylation

Cited by 55 publications

References 46 publications

Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression

Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression

Active DNA demethylation by DNA repair: Facts and uncertainties

Reduced DNA methylation patterning and transcriptional connectivity define human skin aging

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