Co-repressor CBFA2T2 regulates pluripotency and germline development

Abstract

SUMMARY Developmental specification of germ cells lies at the core of inheritance as germ cells contain all of the genetic and epigenetic information transmitted between generations. The critical developmental event distinguishing germline from somatic lineages is the differentiation of primordial germ cells (PGCs)1,2, precursors of sex specific gametes that produce an entire organism upon fertilization. Germ cells toggle between uni- and pluripotent states as they exhibit their own “latent” form of pluripotency. For example, PGCs express a number of transcription factors (TFs) in common with embryonic stem cells (ESCs), including OCT4, SOX2, NANOG and PRDM142–4. A biochemical mechanism by which these TFs converge on chromatin to produce the dramatic rearrangements underlying ESC- and PGC-specific transcriptional programs remains poorly understood. Here, we discover a novel co-repressor protein, CBFA2T2, that regulates pluripotency and germline specification. Cbfa2t2−/− mice display severe defects in PGC maturation and epigenetic reprogramming. CBFA2T2 forms a biochemical complex with PRDM14, a germline-specific transcription factor. Mechanistically, CBFA2T2 oligomerizes to form a scaffold upon which PRDM14 and OCT4 are stabilized on chromatin. Thus, in contrast to the traditional “passenger” role of a co-repressor, CBFA2T2 functions synergistically with TFs at the crossroads of the fundamental developmental plasticity between uni- and pluripotency

Expanding the Circuitry of Pluripotency by Selective Isolation of Chromatin-Associated Proteins

“…These include Nanog, β-catenin, Prdm14, Zfp42 (Rex1), Tcf7l1(Tcf3), Tbx3, and Kdm3a (Jmjd1a). Interestingly, Cbfa2t2, a transcriptional corepressor not previously known to interact with OSN, was identified very recently as a protein that regulates pluripotency and germline specification in mice by providing a scaffold to stabilize PRDM14 and OCT4 on chromatin (Tu et al., 2016). This is not only fully consistent with our observation of Cbfa2t2 in the OSN network but also provides an independent functional validation of our data.…”

Retinoic acid signaling in regulation of meiosis during embryonic development in mice

“…It could be rationalized that Wnt signaling might be required for making epiblast cells competent for responding to BMP signaling to initiate PGC fate specification. Additionally, PRDM14 interacts with MTGR1 (also called CBFA2T2) and together recruits HDACs (histone deacetylases) for inducing gene silencing (Nady et al, 2015;Tu et al, 2016). The PGC competent epiblast cells are initially directed toward somatic fate, but a three pronged repressive activity of Prdm1, Prdm14, and Tcfap2c actively suppresses the expression of somatic genes and promotes PGC specification (Ohinata et al, 2005;Weber et al, 2010;Yamaji et al, 2008).…”

“…PRDM14 protein has been shown to interact with the protein SUZ12, which is a component of PRC2 (polycomb repressive complex 2), and add a repressive mark in the form of H3K27me3 . Additionally, PRDM14 interacts with MTGR1 (also called CBFA2T2) and together recruits HDACs (histone deacetylases) for inducing gene silencing (Nady et al, 2015;Tu et al, 2016). Although signaling to induce PGC specification is active in the posterior epiblast, the anterior visceral endoderm secretes anti-BMP signaling factors that inhibit PGC induction in the anterior epiblast and thus restrict PGC induction to posterior epiblast.…”

DNA (De)Methylation: The Passive Route to Naïvety?

“…This suggests possible differences between events in pluripotent cells in vitro and reprogramming events in vivo [14]. Another direct target of Prdm14 is Glp, an important co-factor for the histone methyltransferase G9a [13,15], which is known to deposit H3K9me2 modification. Previously reported upregulation of Prdm14 in 2i conditions [3,4] may thus lead to observed lower Glp [3] and hence lower H3K9me2 [3,9,10] Glp repressed by Prdm14…”