Stem Cells

There’s a new kid on the block of epigenetic marks, and several recent papers indicate that it plays an important role in maintaining the balance between pluripotency and lineage commitment. The new player, 5-hydroxymethylcytosine (5hmC), is an oxidized derivative of the classic DNAmark, 5-methylcytosine (5mC), generated by the TET enzymes. Now, Wu et al. (2011), Ficz et al. (2011), Williams et al. (2011), Xu et al. (2011), and Pastor et al. (2011) provide genome-wide views of 5hmC’s distribution in mouse embryonic stem cells (mESCs) and find that it is largely associated with promoter regions and gene bodies and, depending on the context, can be associated with either active or repressed transcription states. TET depletion influences 5hmC levels and gene expression patterns. According to Ficz et al., TET deficiency reduces expression of several pluripotency-related genes while facilitating the expression of endoderm markers. Consistent with this, Koh et al. (2011) report that TET levels are high in pluripotent cells and decline during differentiation. These changes appear to be regulated directly by the Oct4-Sox2 complex, a core transcriptional mediator of pluripotency, and depletion of TET genes skews lineage specification from its normal balance of endoderm, mesoderm, and ectoderm during differentiation of mESCs. Thus, 5hmC and the TET enzymes are emerging as key dynamic regulators of pluripotency and differentiation. This knowledge may be useful in ongoing endeavors to direct pluripotent cells to specific cell types. Wu, H., et al. (2011). Genes Dev. 25, 679–684. Ficz, G., et al. (2011). Nature 473, 398–402. Xu, Y., et al. (2011). Mol. Cell, in press. Published online April 20, 2011. 10.1016/j.molcel.2011.04.005. Williams, K., et al. (2011). Nature 473, 343–348. Pastor, W.A., et al. (2011). Nature 473, 394–397. Koh, K.P., et al. (2011). Cell Stem Cell 8, 200–213.