Pluripotency and Epigenetic Factors in Mouse Embryonic Stem Cell Fate Regulation

Abstract

c Embryonic stem cells (ESCs) are characterized by their ability to self-renew and to differentiate into all cell types of a given organism. Understanding the molecular mechanisms that govern the ESC state is of great interest not only for basic research-for instance, ESCs represent a perfect system to study cellular differentiation in vitro-but also for their potential implications in human health, as these mechanisms are likewise involved in cancer progression and could be exploited in regenerative medicine. In this minireview, we focus on the latest insights into the molecular mechanisms mediated by the pluripotency factors as well as their roles during differentiation. We also discuss recent advances in understanding the function of the epigenetic regulators, Polycomb and MLL complexes, in ESC biology. Within 2 days after fertilization, a mouse oocyte has undergone a series of cellular divisions and has developed into the morula embryo. The totipotent cells within the morula then divide and further specialize to form the hollow blastocyst sphere. The outer layer of the blastocyst contains the trophectoderm cells, while the inner cell mass (ICM) contains the pluripotent embryonic stem cells (ESCs) that will give rise in the developing embryo to all cell types of the three germ layers-ectoderm, mesoderm, and endoderm. Mouse ESCs were first isolated by Evans and Kaufman in 1981 (1) and have since been extensively studied. Under proper cell culture conditions, ESCs can divide and self-renew indefinitely, yet under differentiation stimuli, ESCs can also differentiate into virtually all cell types of the organism.Which molecular mechanisms control the decision of ESCs to self-renew or to differentiate? During the last decades, several transcription factors have been identified to be essential for ESC pluripotency. These transcription factors regulate pluripotency by a so-called "pluripotency network" that regulates their own expression and coregulates the expression of other key transcription factors through multiple mechanisms. Interestingly, pluripotency is controlled at the transcriptional levels of genes through specific signaling pathways and epigenetic factors.Epigenetics is the study of heritable changes in gene expression that are not caused by changes at the DNA sequence level. The Polycomb and MLL (myeloid-lineage leukemia) complexes are two of the best-characterized epigenetic machineries implicated in ESC pluripotency and differentiation. Although pluripotency factors do not physically interact with Polycomb and MLL complexes, they coregulate lineage-specific genes important for ESC differentiation.In this review, we discuss the most recent advances in understanding mouse ESC pluripotency and differentiation, paying particular attention to Oct4, Nanog, and Sox2, as well as to factors involved in the exit from pluripotency. Finally, we discuss the function and the molecular mechanisms of the Polycomb and MLL complexes in mouse ESC pluripotency. MASTER REGULATORS OF ESC IDENTITY: THE Oct4, Sox2, AND Nano...

Epigenetic Remodeling in Male Germline Development

“…They are able to differentiate into all three germ layers under differentiation stimuli [7, 8]. In the maintaining of pluripotency, regulations from transcriptional factors to epigenetic modifications are both crucial [9]. …”

Making gametes from pluripotent stem cells: embryonic stem cells or very small embryonic-like stem cells?

“…Similarly, conditional knockdown of Nanog (32) and SOX2 (33) also induced apoptosis and decreased numbers of migrating PGCs rather than their differentiation. Thus OCT-4, NANOG and SOX2 are crucial for PGCs; form the triumvirate to define pluripotent state (34) and their expression in PGCs reflects pluripotent state of PGCs.…”

Chromatin and Epigenetics at the Forefront: Finding Clues among Peaks

“…Despite having a dispensable role during self-renewal, Polycomb complexes are required to engage appropriated differentiation programs (23). Recent work from Luciano Di Croce's group (CRG, Spain) has revealed the functionality of the different PRC1 subcomplexes during ESC differentiation (24)(25)(26).…”