A simple model system with synchronous differentiation would provide an ideal platform to address these issues. The in vitro differentiation system of mouse embryonic stem cells (mESCs) (Box 1, Glossary; Box 2) provides one such model (Niwa, 2010).
This suggests that the transition from the naïve to the primed state might not be a direct process. Recently, an intermediate state between naïve and primed was proposed.
そうした自然発生の解明には、mESCs や EpiSCsの人工的誘導細胞の研究が貢献してきたと総説イントロダクションに書かれています。 The dynamic changes in TF binding between mESCs and EpiSCs may support the existence of such an intermediate state as defined by a stable TF network
During mouse development, a single, totipotent cell divides repeatedly to give rise to a few billion cells, which differentiate into a few hundred different cell types. Differentiation is the process by which a cell changes phenotype and becomes increasingly specialized. Cell phenotypes are defined by particular combinations of genes expressed in a cell type-dependent manner (Armit et al., 2017). The selection of these combinations is mainly driven by cell type-specific transcription factors (TFs), which in turn are regulated by other TFs that integrate and respond to extracellular signals in order to maintain cell phenotype (Davidson, 1993). Thus, TFs form a network in which each TF is reciprocally regulated to maintain its balanced expression.
A TF network often forms part of a gene regulatory network (Box 1, Glossary). Gene regulatory networks are divided into functional subcircuits (Davidson, 2010) and consist of multiple layers of regulatory mechanisms at the epigenetic, topological and transcriptional level. The epigenetic regulation of chromatin accessibility is thought to be important for maintaining the irreversibility of a cell's differentiated status under normal physiological conditions (Perino and Veenstra, 2016). The topological regulation of chromatin is also believed to control global gene expression patterns in organisms (Acemel et al., 2017); however, the degree to which these regulatory mechanisms actively determine specific cell types is unclear. By contrast, TF networks have been shown to play a pivotal role in defining cell types, which is reflected in the ability of certain TFs to instruct changes in cell phenotype when ectopically expressed in various contexts (Niwa, 2007; Morris, 2016). The discovery of MyoD (Myod1), for example, was a key finding in this field as it demonstrated the power of a single TF to define cell phenotype (Davis et al., 1987). This example might be somewhat of a rarity, however, since in general the potential of a single cell-type-specific TF to instruct fate is limited, and it often only regulates differentiation in a particular context. More commonly, specific combinations of TFs are required to instruct cell fate, most famously during the reprogramming of differentiated somatic cells to pluripotent stem cells, which requires a combination of four TFs (Takahashi and Yamanaka, 2006). Other combinations of TFs have also been used to induce direct lineage reprogramming, whereby a cell transitions from one cell type to another without returning to a pluripotent state (Morris, 2016).
より一般的には、TFの特定の組み合わせが細胞運命を指示するために必要であり、最も有名なのは、分化した体細胞を多能性幹細胞に再プログラミングする際であり、4つのTFの組み合わせが必要です（Takahashi and Yamanaka、2006）。 TFの他の組み合わせも、直接的な系統の再プログラミングを誘発するために使用されています。多能性状態に戻らずに、ある細胞タイプから別の細胞タイプに移行します（Morris、2016年）。
These findings raised a key question: why are multiple TFs required to artificially change a cellular phenotype? To answer this question, we need to know how TFs function in a cell to define a phenotype. During differentiation, multiple TFs are known to cooperate with each other to activate transcription of their target genes (Whyte et al., 2013). To stably maintain a certain cell type, multiple TFs form a network that maintains their own expression, as well as that of cell type-specific genes as a downstream subcircuit (Davidson, 2010). While these broad principles have been established for a number of years, specific issues, such as what determines the exact number of TFs required to form a cell type-specific TF network, and how TF networks are sequentially replaced during differentiation, remain unanswered. A simple model system with synchronous differentiation would provide an ideal platform to address these issues. The in vitro differentiation system of mouse embryonic stem cells (mESCs) (Box 1, Glossary; Box 2) provides one such model (Niwa, 2010). In this Review, I focus on studies that analyze the role of TFs in regulating mESC self-renewal and differentiation, and summarize the mechanisms involved in the functioning and transitioning of TF networks.
Box 2. Transition of mESCs toward multiple lineages The pluripotent states at early and late developmental stages are distinct, and are designated as the naïve and primed pluripotent states (Nichols and Smith, 2009). mESCs are in the naïve pluripotent state that mimics the character of late stage epiblast of blastocyst stage embryos (Boroviak et al., 2015), whereas mouse EpiSCs are in the primed pluripotent state that mimics the character of the late post-implantation stage epiblast (Brons et al., 2007; Tesar et al., 2007). In the developmental context, the late stage epiblast of blastocyst stage embryos gives rise to the late post-implantation stage epiblast, suggesting that the primed pluripotent state could represent a direct transition from mESCs. Indeed, culturing mESCs in the culture conditions for EpiSCs (i.e. containing activin A and Fgf2) allows their gradual transition over several passages (Guo et al., 2009). However, to date, there is no way to direct a homogeneous transition of mESCs to the primed state within a few days in culture, as is observed in the developmental context. This suggests that the transition from the naïve to the primed state might not be a direct process. Recently, an intermediate state between naïve and primed was proposed. This state, designated formative pluripotency, is defined by the downregulation of the naïve-specific TFs without the activation of the lineage-primed TFs that are activated in the primed state (Smith, 2017). Although PSCs in the formative state have not been captured stably, epiblast-like cells obtained transiently by the culture of mESCs could be close to it (Hayashi et al., 2011). The dynamic changes in TF binding between mESCs and EpiSCs may support the existence of such an intermediate state as defined by a stable TF network (see figure; dashed lines indicate events that can be induced under artificial conditions) (Matsuda et al., 2017). The transition to the embryonic cell lineages – definitive endoderm, ectoderm and mesoderm – could occur directly from the primed state TF network, but never from the naïve state TF network.
ため息さんグーグル訳 ＞マウスの発育中、単一の全能性細胞が繰り返し分裂して数十億個の細胞を生じ、それが数百の異なる細胞型に分化します。分化は、細胞が表現型を変化させ、ますます特殊化するプロセスです。細胞の表現型は、細胞の種類に依存して発現する遺伝子の特定の組み合わせによって定義されます（Armit et al。、2017）。これらの組み合わせの選択は、主に細胞型特異的転写因子（TF）によって駆動され、細胞表現型を維持するために細胞外シグナルを統合して応答する他のTFによって制御されます（Davidson、1993）。したがって、TFは、バランスの取れた表現を維持するために各TFが相互に制御されるネットワークを形成します。
Indeed, culturing mESCs in the culture conditions for EpiSCs (i.e. containing activin A and Fgf2) allows their gradual transition over several passages (Guo et al., 2009). However, to date, there is no way to direct a homogeneous transition of mESCs to the primed state within a few days in culture, as is observed in the developmental context. This suggests that the transition - -