The NuRD component Mbd3 is required for pluripotency of embryonic stem cells

Abstract

Cells of early mammalian embryos have the potential to develop into any adult cell type, and are thus said to be pluripotent. Pluripotency is lost during embryogenesis as cells commit to specific developmental pathways. Although restriction of developmental potential is often associated with repression of inappropriate genetic programmes, the role of epigenetic silencing during early lineage commitment remains undefined. Here, we used mouse embryonic stem cells to study the function of epigenetic silencing in pluripotent cells. Embryonic stem cells lacking Mbd3 - a component of the nucleosome remodelling and histone deacetylation (NuRD) complex - were viable but failed to completely silence genes that are expressed before implantation of the embryo. Mbd3-deficient embryonic stem cells could be maintained in the absence of leukaemia inhibitory factor (LIF) and could initiate differentiation in embryoid bodies or chimeric embryos, but failed to commit to developmental lineages. Our findings define a role for epigenetic silencing in the cell-fate commitment of pluripotent cells.

NuRD Blocks Reprogramming of Mouse Somatic Cells into Pluripotent Stem Cells

“…Thus, depletion of Mbd3/ NuRD upregulates the expression of key iPSC promoting factors, facilitating the generation of pluripotent cells. Apparently, modulatory activity of NuRD constrains differentiation of ESCs thereby directly controlling their immediate differentiation potential [14][15][16]19]. Depletion of other core components of the NuRD complex, such as Mbd2 or Mi2/CHD4, improved iPSC generation to the same extent as knockdown of Mbd3 (unpublished results).…”

“…Overexpression of Nanog is sufficient for maintaining the pluripotency of mESCs in the absence of LIF and ensures direct reprogramming of somatic cells to the pluripotent ground state [15,16]. Therefore, fine-tuning of Nanog levels is necessary for balancing differentiation and self-renewal of ESCs.…”

“…Moreover, Mbd3/NuRD directly regulates expression of pluripotency genes in ESCs to modulate transcriptional heterogeneity and maintain ESC lineage commitment [14]. ESCs lacking Mbd3/NuRD retain Oct4 expression in the absence of the cytokine leukemia inhibitory factor (LIF) and have a restricted potential to differentiate [15,16], suggesting an important function of Mbd3/NuRD in the establishment or maintenance of pluripotency. Conversely, inhibitors of histone deacetylases or DNA methyltransferases enhance reprogramming, suggesting that the complete erasure of epigenetic marks is required to overcome the barrier to pluripotency [7][8][9].…”

Cdx2Efficiently Induces Trophoblast Stem-Like Cells in Naïve, but Not Primed, Pluripotent Stem Cells

“…Differences in the transcriptomes, proteomes, and chromatin states of ESCs and EpiSCs have been compared [62][63][64][65]. Notably, NuRD-dependent methylation prevents ESCs from spontaneously acquiring trophoblast fate [66][67][68][69]. However, it is not known whether NuRD methylation maintains this lineage barrier in EpiSCs.…”

Pluripotency in the Embryo and in Culture

“…Table 1 lists key factors that have been functionally validated as playing pivotal roles, while Figure 4 presents a Kaji et al 2006Kaji et al , 2007 Abbreviations: ICM, inner cell mass; LIF, leukemia inhibitor factor; RNAi, RNA interference. (Niwa et al 2000).…”