Role of Oct4 in maintaining and regaining stem cell pluripotency

Abstract

Pluripotency, a characteristic of cells in the inner cell mass of the mammalian preimplantation blastocyst as well as of embryonic stem cells, is defined as the ability of a cell to generate all of the cell types of an organism. A group of transcription factors is essential for the establishment and maintenance of the pluripotent state. Recent studies have demonstrated that differentiated somatic cells could be reverted to a pluripotent state by the overexpression of a set of transcription factors, further highlighting the significance of transcription factors in the control of pluripotency. Among these factors, a member of the POU transcription factor family, Oct4, is central to the machinery governing pluripotency. Oct4 is highly expressed in pluripotent cells and becomes silenced upon differentiation. Interestingly, the precise expression level of Oct4 determines the fate of embryonic stem cells. Therefore, to control the expression of Oct4 precisely, a variety of regulators function at multiple levels, including transcription, translation of mRNA and post-translational modification. Additionally, in cooperation with Sox2, Nanog and other members of the core transcriptional regulatory circuitry, Oct4 activates both protein-coding genes and noncoding RNAs necessary for pluripotency. Simultaneously, in association with transcriptional repressive complexes, Oct4 represses another set of targets involved in developmental processes. Importantly, Oct4 can re-establish pluripotency in somatic cells, and proper reprogramming of Oct4 expression is indispensable for deriving genuine induced pluripotent stem cell lines. In the past several years, genome-wide identification of Oct4 target genes and Oct4-centered protein interactomes has been reported, indicating that Oct4 exerts tight control over pluripotency regulator expression and protects embryonic stem cells in an undifferentiated state. Nevertheless, further investigation is required to fully elucidate the underlying molecular mechanisms through which Oct4 maintains and reinitiates pluripotency. Systemic and dynamic exploration of the protein complexes and target genes associated with Oct4 will help to elucidate the role of Oct4 more comprehensively.

Figure 1

Precise control of Oct4 expression at multiple levels. The chromatin modifier Paf1C increases Oct4 expression by relaxing the compact chromatin, while G9a adds a repressive mark and recruits heterochromatin protein 1 (HP1), leading to a compact chromatin configuration. Subsequently, Dnmt3a/b methylates the Oct4 promoter to permanently inactivate Oct4 expression. This process is enhanced by Cdk2ap1 interacting with Mbd3. At the transcription level, two sets of transcription factors and nuclear receptors function antagonistically: one set (including Esrrb, LRH-1, Oct4, Sox2 and Sall4) activates Oct4 expression, while the other set (including germ cell nuclear factor (GCNF) and Tr2) represses its expression. After transcription, Lin28 recruits RNA helicase A to promote the translation of Oct4 mRNA, while miRNAs (including miR-134 and miR-470) cause its decay. In addition, several post-translational modifications (such as ubiquitination (Ub), sumoylation and phosphorylation (P)) are added to the Oct4 protein after it is translated and influence the activity and stability of Oct4 proteins. SUMO, small ubiquitin-related modifier.

Figure 2

Oct4 interacts with various partners and regulates different target sets to carry out its functions. Depending on its associated partners, Oct4 can either activate or repress its target genes. When associated with factors such as Sox2, Nanog and Sall4 at regulatory elements, Oct4 usually exerts stimulatory effects on gene expression. Additionally, Oct4 can repress developmental genes through interacting with repressors (for example, NuRD and PRC1). Through regulating various targets, Oct4 has versatile effects on pluripotency: it maintains self-renewal and pluripotency by activating its own expression and that of factors such as Sox2 and Nanog; through modulating the expression or function of development-associated genes - such as Stk40, Cdx2, Eset and FoxD3 - Oct4 prevents the differentiation of pluripotent stem cells; it can also influence other aspects of embryonic stem cells (ESCs), including cell cycle and X-chromosome inactivation, through various effectors (for example, miR-302a, Ctcf ). ExEn, extraembryonic endoderm.