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An Epigenetic Tet a Tet with Pluripotency

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An Epigenetic Tet a Tet with Pluripotency CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Cell Stem Cell Previews An Epigenetic Tet a Tet with Pluripotency Jo¨ rn Walter1,* 1Saarland University, FR 8.3 Biosciences, Laboratory of EpiGenetics, Campus, Building A2.4, Postbox 151150, D-66041 Saarbru¨ cken, Germany *Correspondence: [email protected] DOI 10.1016/j.stem.2011.01.009 DNA and chromatin-modifying enzymes establish an ESC/iPSC-specific epigenomic landscape that is linked to a network of pluripotency genes and influences differentiation potential. In this issue of Cell Stem Cell, Koh et al. (2011) highlight Tet1 and Tet2 as key players in this network of coordinated genetic and epigenetic control. DNA methylation and chromatin modifi- ally characterized the cells by in vitro despite the presence of functional Tet1 cations serve as important epigenetic differentiation and in vivo teratoma forma- and Tet2 enzymes. The data by Koh control layers on top of the genome tion. They observed that upon ESC differ- et al. now support the view that Tet1 and sequence. They determine the chromatin entiation, both Tet1 and Tet2 are down- Tet2 function exclusively through the structure and regulate gene expression. regulated, while Tet3 is upregulated. generation of 5hmC and act as important Early embryonic development and the Conversely, Tet3 expression declines players in differentiation processes. The generation of pluripotent cells are marked and Tet1 and Tet2 become expressed future generation and analysis of Tet1- by dramatic reprogramming of genome- when fibroblasts were reprogrammed to and Tet2-deficient ESCs should permit wide and gene-specific alterations in generate iPSCs, supporting the model the testing of this hypothesis. DNA methylation. The recent discovery that Tet1 and Tet2 are associated with, Most remarkably, Tet1 and Tet2 appear of a sixth base, 5-hydroxymethylcytosine and important for, the pluripotent state. to be downstream of, and directly (5hmC), hinted that the mechanisms Differential knockdown (KD) experiments controlled by, the Oct4/Sox2 network, as responsible for the oxidation of 5-methyl- suggest that both dioxygenases act they contain Oct4 and Sox2 binding sites cytosine (5mC) to 5hmC might offer a clue together in converting 5mC into 5hmC, and are downregulated in Oct4/Sox2- to understanding processes of epigenetic although the specific targets of Tet1 and depleted cells. Hence, the generation of control. Indeed, the three 2-oxogluterate Tet2 may not completely overlap. In 5hmC by Tet proteins is directly linked to (2OG)- and Fe(II)-dependent dioxyge- further elegant experiments using KD the pluripotency network. Still, how exactly nases, Tet1, Tet2, and Tet3, were found depletion, the authors uncover a sophisti- Tet activity affects the control of gene to be able to mediate the transition of cated regulation of Tet1 and Tet2. In differ- expression remains an open question. 5mC to 5hmC, and a substantial amount entiating ESCs, Tet1 and Tet2 appear to Tet1 depletion causes changes in the of all methylcytosine appears to be con- control distinct sets of early differentiation expressionofLeftyandElf5;atrophoblastic verted by this trio of enzymes in various genes and affect distinct signaling path- commitment marker A bisulfite analysis of tissues/cells (Globisch et al., 2010, Szwa- ways. While Tet1 depletion alters Lefty both genes reveals a complex picture. gierczak et al., 2010; Ko et al. 2010). In line expression, coupled with a skewed meso- While Tet1 depletion causes a decrease in with a recent publication (Ito et al., 2010), derm/endoderm bias and leading to Lefty expression along with an increase in in this issue Koh et al. (2011) report that trophoblast lineage commitment, Tet2 DNA methylation (note that the bisulfite Tet1 and Tet2, but not Tet3, are ex- depletion promotes a tendency toward assay used does not distinguish between pressed in embryonic stem cells (ESCs). neuroectoderm differentiation. Of note, 5mC or 5hmC), the upregulation of Elf5 In a detailed functional analysis, Koh and in contrast with a previous report (Ito was not linked to a Tet1-dependent deme- et al. furthermore unravel a new link et al., 2010), the authors did not observe thylation effect (Koh et al., 2011). between Tet1 and Tet2 expression, its an upstream impact on the pluripotency Together, the findings of Koh et al. control by the pluripotency network, and cascade following the KD of Tet1 or Tet2. (2011) and Ito et al. (2010) represent the differentiation potential of ESCs. Their Specifically, depletion of Tet1 and/or important advances with respect to our findings directly link mechanisms of Tet2 led to neither morphologic changes understanding of epigenomic control genetic and epigenetic control and nor reduced viability in the targeted during early mammalian development. suggest an important role for 5hmC in ESCs, nor expression differences in pluri- Already, their results link three important ESC maintenance and differentiation. potency factors Oct4, Sox2, and Nanog. development steps (the formation of To study the role and regulation of Tet These findings are in line with observa- pluripotent stem cells in the embryo, the genes, Koh and colleagues used a variety tions made in Dnmt1-3 triple knockout maintenance of pluripotency, and the of methods, altering the expression of cells (TKO), i.e., cells without detectable differentiation into three germ layers) to Tet1, Tet2, Tet3, and several known pluri- DNA methylation. 5mC is the substrate a sophisticated network control mediated potency factors, such as Oct4, Sox2, and for Tet1 and Tet2, and a recent study by 5hmC-generating enzymes. The cur- Nanog. Following such manipulations, (Szwagierczak et al., 2010) showed that rent picture suggests that Tet1 and, to they monitored expression and function- TKO ESCs have no detectable 5OH, a lesser extent, Tet2 are key players in Cell Stem Cell 8, February 4, 2011 ª2011 Elsevier Inc. 121 Cell Stem Cell Previews pluripotent cells, while Tet3 (presumably this mark is likely to be distinct in ESCs the lengthy list of unresolved questions, in combination with Tet1 or Tet2) may and in actively differentiating cells, given the (re)discovery of the sixth base and function to control hydroxylation in differ- that Tet1 and Tet2 are the predominant of the regulation of Tet enzymes will entiated cells. Nonetheless, Koh et al. enzymes expressed in these populations greatly influence our understanding of leave us with several lingering issues and, relatively speaking, Tet3 is absent. epigenetic control in stem cells. The time that need to be addressed before we will Technologies that achieve simulta- for new epigenetic concepts in stem cell understand how DNA methylation and neous detection and location of both research is on the horizon. DNA hydroxylation are functionally 5mC and 5hmC are only beginning to be embedded in the epigenetic and genetic developed, but with these new tools the REFERENCES network control of pluripotency. First of field may soon see ESC profiles that will all, it will be important to precisely deter- hopefully point to answers for these ques- Globisch, D., Mu¨ nzel, M., Mu¨ ller, M., Michalakis, S., Wagner, M., Koch, S., Bru¨ ckl, T., Biel, M., and mine the location of 5hmC modifications tions. ChIP and mass spectrometry Carell, T. (2010). PLoS ONE 5, e15367. in ESCs, as well as the gene specificity experiments with individual Tet enzymes of individual Tet enzymes. Furthermore, in ESCs will provide insight into interact- Ito, S., D’Alessio, A.C., Taranova, O.V., Hong, K., Sowers, L.C., and Zhang, Y. (2010). Nature 466, the targeting mechanisms that direct indi- ing partners and enzyme binding loca- 1129–1133. vidual Tets to specific regions/genes tions. RNA-Seq in combination with direct Ko, M., Huang, Y., Jankowska, A.M., Pape, U.J., need to be investigated. Finally, it remains 5hmC mapping techniques (e.g., through Tahiliani, M., Bandukwala, H.S., An, J., Lamperti, to be seen how hydroxylation itself modu- hMeDIP) in ESCs depleted for either of E.D., Koh, K.P., Ganetzky, R., et al. (2010). Nature lates gene expression. the Tet enzymes will provide further 468, 839–843. Toward these goals, Song et al. (2011) answers as to possible mechanistic links. Koh, K.P., Yabuuchi, A., Rao, S., Huang, Y., have recently presented one approach But as stated by Koh et al. (2011), the rela- Cunniff, K., Nardone, J., Laiho, A., Tahiliani, M., Sommer, C.A., Mostoslavsky, G., et al. (2011). designed to locate 5hmC modifications tion between Tet function and DNA Cell Stem Cell 8, this issue, 200–213. in the genome. Their study suggests that methylation is (apparently more) complex in adult brain cells, which express Tet3, and not necessarily always promoter Song, C.X., Szulwach, K.E., Fu, Y., Dai, Q., Yi, C., Li, X., Li, Y., Chen, C.H., Zhang, W., Jian, X., 5hmC is enriched, relative to 5mC, in in- directed. It remains an open question as et al. (2011). Nat. Biotechnol. 29, 68–72. tergenic regions and both upstream and to which direct or indirect mechanisms Szwagierczak, A., Bultmann, S., Schmidt, C.S., downstream of the transcription start link the presence and absence of 5hmC Spada, F., and Leonhardt, H. (2010). Nucleic Acids site (TSS). However, the distribution of to the control of gene expression. Despite Res. 38, e181. A Comprehensive Transcriptional Landscape of Human Hematopoiesis Barbara L. Kee1,* 1Committees on Immunology, Cancer Biology, and Development, Regeneration and Stem Cell Biology Department of Pathology, The University of Chicago, Chicago IL 60637, USA *Correspondence: [email protected] DOI 10.1016/j.stem.2011.01.006 Recently in Cell, Novershtern et al. (2011) reported a comprehensive transcriptome analysis of human hema- topoiesis, combined with sophisticated bioinformatics analysis and high-throughput DNA binding data for multiple transcription factors. The resulting map of regulatory interactions controlling stem cell differentiation provides a valuable resource for identification of novel hematopoietic regulators.
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