The role of PRDM14 in epigenetic reprogramming and mouse development
PRDM14 is a transcriptional regulator specifically expressed in preimplantation mouse embryos, primordial germ cells (PGCs) and pluripotent stem cells. PRDM14 is essential for mouse germ cell development, for naïve pluripotency in mouse embryonic stem (ES) cells and also plays a critical role for pluripotency in humans ES cells. On a mechanistic level, PRDM14 acts by repressing its negative target genes by recruiting polycomb repressive complex 2 (PRC2), but it can also activate target genes depending on its interacting proteins. Thereby, PRDM14 controls processes like epigenetic reprogramming in PGCs, represses somatic lineage-specific genes and DNA-methyltransferases in pluripotent stem cells and activates expression of pluripotency genes.
In our previous work (Payer et al., Molecular Cell 2013), we have shown that PRDM14 controls X-chromosome reactivation in mouse blastocysts and during iPS cell reprogramming (Figure 2). It does this by repressing Rnf12, which is an activator of the Xist noncoding RNA gene, the master regulator of X-chromosome inactivation. Besides this role in the X-reactivation pathway, we have identified general, X-reactivation-independent functions of PRDM14 for mouse development and iPS cell reprogramming. In our laboratory we are now interested in further defining the roles, which PRDM14 plays in its different expression domains both for X-chromosome reactivation and beyond.
Figure 2: Model for Xist-regulation in blastocysts and during iPSC reprogramming. In early embryos and differentiated cells like fibroblasts (top) the activators Rnf12 and Jpx induce Xist expression and X-inactivation. X-reactivation occurs during epiblast (Epi) maturation and iPSC reprogramming (bottom), when the germ cell factor PRDM14 binds with other pluripotency factors (not shown) to Xist intron 1, a process enhanced by Tsix expression. Furthermore, PRDM14 binds upstream Rnf12, where it recruits the PRC2 complex, resulting in silencing of Rnf12 by H3K27me3. These events, together with a lack of Jpx expression, result in silencing of Xist. Adapted from Payer et al., Mol. Cell (2013).