Epigenetic reprogramming in mouse primordial germ cells

Genome-wide epigenetic reprogramming in mammalian germ cells, zygote and early embryos, plays a crucial role in regulating genome functions at critical stages of development. We show here that mouse primordial germ cells (PGCs) exhibit dynamic changes in epigenetic modifications between days 10.5 and 12.5 post coitum (dpc). First, contrary to previous suggestions, we show that PGCs do indeed acquire genome-wide de novo methylation during early development and migration into the genital ridge. However, following their entry into the genital ridge, there is rapid erasure of DNA methylation of regions within imprinted and non-imprinted loci. For most genes, the erasure commences simultaneously in PGCs in both male and female embryos, which is completed within 1 day of development. Based on the kinetics of this process, we suggest that this is an active demethylation process initiated upon the entry of PGCs into the gonadal anlagen. The timing of reprogramming in PGCs is crucial since it ensures that germ cells of both sexes acquire an equivalent epigenetic state prior to the differentiation of the definitive male and female germ cells in which new parental imprints are established subsequently. Some repetitive elements, however, show incomplete erasure, which may be essential for chromosome stability and for preventing activation of transposons to reduce the risk of germline mutations. Aberrant epigenetic reprogramming in the germ line would cause the inheritance of epimutations that may have consequences for human diseases as suggested by studies on mouse models.     

Epigenetic reprogramming of the genome--from the germ line to the embryo and back again.

Mammalian parental genomes are not functionally equivalent, and both a maternal and paternal contribution is required for normal development. The differences between the parental genomes are the result of genomic imprinting--a form of gene regulation that results in monoallelic expression of imprinted genes. Cis-regulatory elements at imprinted loci are responsible for directing allele-specific epigenetic marks required for correct gene expression. This cis information must be interpreted at various points in development, including in the germline where existing imprints are erased and reset. Imprints must also be maintained during preimplantation development, when the genome undergoes dramatic global epigenetic changes.     

Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells

Epigenetic modifications are crucial for the identity and stability of cells, and, when aberrant, can lead to disease. During mouse development, the genome-wide epigenetic states of pre-implantation embryos and primordial germ cells (PGCs) undergo extensive reprogramming. An improved understanding of the epigenetic reprogramming mechanisms that occur in these cells should provide important new information about the regulation of the epigenetic state of a cell and the mechanisms of induced pluripotency. Here, we discuss recent findings about the potential mechanisms of epigenetic reprogramming, particularly genome-wide DNA demethylation, in pre-implantation mouse embryos and PGCs.     

细胞重编程中的表观遗传分子机制

成体细胞可以通过核移植、细胞融合或者特定因子导入的方式实现重编程回到多能性状态。在重编程的过程中,表观遗传水平的调控机制起到了非常关键的作用。通过回顾重编程的研究进展来探讨表观遗传学在重编程中的调控机制。     

Epigenetic reprogramming in plant reproductive lineages

Monoecious flowering plants produce both microgametophytes (pollen) and megagametophytes (embryo sacs) containing the male and female gametes, respectively, which participate in double fertilization. Much is known about cellular and developmental processes giving rise to these reproductive structures and the formation of gametes. However, little is known about the role played by changes in the epigenome in dynamically shaping these defining events during plant sexual reproduction. This has in part been hampered by the inaccessibility of these structures-especially the female gametes, which are embedded within the female reproductive tissues of the plant sporophyte. However, with the recent development of new cellular isolation technologies that can be coupled to next-generation sequencing, a new wave of epigenomic studies indicate that an intricate epigenetic regulation takes place during the formation of male and female reproductive lineages. In this mini review, we assess the fast growing body of evidence for the epigenetic regulation of the developmental fate and function of plant gametes. We describe how small interfereing RNAs and DNA methylation machinery play a part in setting up unique epigenetic landscapes in different gametes, which may be responsible for their different fates and functions during fertilization. Collectively these studies will shed light on the dynamic epigenomic landscape of plant gametes or 'epigametes' and help to answer important unresolved questions on the sexual reproduction of flowering plants, especially those underpinning the formation of two products of fertilization, the embryo and the endosperm.     

Epigenetic reprogramming in mammalian nuclear transfer

With the exception of lymphocytes, the various cell types in a higher multicellular organism have basically an identical genotype but are functionally and morphologically different. This is due to tissue-specific, temporal, and spatial gene expression patterns which are controlled by genetic and epigenetic mechanisms. Successful cloning of mammals by transfer of nuclei from differentiated tissues into enucleated oocytes demonstrates that these genetic and epigenetic programs can be largely reversed and that cellular totipotency can be restored. Although these experiments indicate an enormous plasticity of nuclei from differentiated tissues, somatic cloning is a rather inefficient and unpredictable process, and a plethora of anomalies have been described in cloned embryos, fetuses, and offspring. Accumulating evidence indicates that incomplete or inappropriate epigenetic reprogramming of donor nuclei is likely to be the primary cause of failures in nuclear transfer. In this review, we discuss the roles of various epigenetic mechanisms, including DNA methylation, chromatin remodeling, imprinting, X chromosome inactivation, telomere maintenance, and epigenetic inheritance in normal embryonic development and in the observed abnormalities in clones from different species. Nuclear transfer represents an invaluable tool to experimentally address fundamental questions related to epigenetic reprogramming. Understanding the dynamics and mechanisms underlying epigenetic control will help us solve problems inherent in nuclear transfer technology and enable many applications, including the modulation of cellular plasticity for human cell therapies.     

Epigenetic reprogramming during tissue regeneration

Epigenetic control of gene regulation is fundamental to the maintenance of cellular identities during all stages of metazoan life. Tissue regeneration involves cellular reprogramming processes, like dedifferentiation, re-differentiation, and trans-differentiation. Hence, in these processes epigenetic maintenance of gene expression programs requires a resetting through mechanisms that we are only beginning to understand. Here we summarize the current status of these studies, in particular regarding the role of epigenetic mechanisms of cellular reprogramming during tissue regeneration.     

Epigenetic reprogramming: roads to pluripotency

Epigenetic reprogramming provides valuable resources for customized pluripotent stem cells generation, which are thought to be important bases of future regenerative medicine. Here we review the commonly used methods for epigenetic reprogramming: somatic cell nuclear transfer, cell fusion, cell extract treatment, inducing pluripotency by defined molecules, and briefly discuss their advantages and limitations. Finally we propose that mechanisms underlying epigenetic reprogramming and safety evaluation platform will be future research directions.     

Epigenetic reprogramming: Prdm14 hits the accelerator

Cell Stem Cell 10 4, 425–439 (2012); published online April062012The release of epigenetic boundaries during epigenetic reprogramming is poorly understood. In the recent issue of Cell Stem Cell Journal, Gillich and colleagues identify a unique role for Prdm14 in the acceleration of this process (Gillich et al, 2012).Pluripotent stem cells can be established from pre-implantation blastocyst embryos (embryonic stem cells, ESCs) as well as from the post-implantation epiblast stem cells (EpiSCs; Chenoweth et al, 2010). Murine ESCs and EpiSCs both express central pluripotency factors such as Oct4, Nanog and Sox2, yet the different developmental origins of these two cell types is clearly reflected in their molecular, epigenetic and functional properties. Murine ESCs appear to exist in a unique ‘naive'' state reminiscent of the pre-implantation epiblast. They are characterized by the expression of germ cell–related genes, a remarkably open chromatin structure with two active X chromosomes, and the functional ability to contribute to chimera formation upon blastocyst complementation (Nichols and Smith, 2011). In contrast, EpiSCs reflect the properties of the post-implantation epiblast, characterized by low-level expression of early determinants of somatic differentiation, a near-absence of germ cell gene expression, inactivation of one of the X chromosomes and negligible ability to support the development of chimeric mice. The conversion of primed to naive pluripotent state requires the release of epigenetic restrictions that are established in the post-implantation epiblast. It is thus a reprogramming process akin to the derivation of induced pluripotent stem cells (iPSCs) from somatic cells. The results on Prdm14 from Gillich and colleagues offer new insights into the underlying molecular mechanisms governing epigenetic reprogramming.     

Epigenetic predisposition to reprogramming fates in somatic cells

Reprogramming to pluripotency is a low‐efficiency process at the population level. Despite notable advances to molecularly characterize key steps, several fundamental aspects remain poorly understood, including when the potential to reprogram is first established. Here, we apply live‐cell imaging combined with a novel statistical approach to infer when somatic cells become fated to generate downstream pluripotent progeny. By tracing cell lineages from several divisions before factor induction through to pluripotent colony formation, we find that pre‐induction sister cells acquire similar outcomes. Namely, if one daughter cell contributes to a lineage that generates induced pluripotent stem cells (iPSCs), its paired sibling will as well. This result suggests that the potential to reprogram is predetermined within a select subpopulation of cells and heritable, at least over the short term. We also find that expanding cells over several divisions prior to factor induction does not increase the per‐lineage likelihood of successful reprogramming, nor is reprogramming fate correlated to neighboring cell identity or cell‐specific reprogramming factor levels. By perturbing the epigenetic state of somatic populations with Ezh2 inhibitors prior to factor induction, we successfully modulate the fraction of iPSC‐forming lineages. Our results therefore suggest that reprogramming potential may in part reflect preexisting epigenetic heterogeneity that can be tuned to alter the cellular response to factor induction.     

Epigenetic reprogramming in the mammalian embryo: struggle of the clones

During preimplantation development in mammals, distinct epigenetic marks on oocyte and sperm DNA are remodeled to an embryonic pattern. A recent study examining global methylation of repetitive elements in various mammals showed that the reprogramming that occurs during normal preimplantation development is aberrant in cloned embryos.     

Epigenetic reprogramming during plant reproduction and seed development

Epigenetic processes such as DNA methylation are crucial for the development of flowering plants, and for protection of genome integrity via silencing of transposable elements (TEs). Recent advances in genome-wide profiling suggest that during reproduction DNA methylation patterns are at least partially transmitted or even enhanced in the next generation to ensure stable silencing of TEs. At the same time, parent-of-origin specific removal of DNA methylation in the accompanying tissue allows imprinted expression of genes. Here we summarize the dynamics of DNA methylation as a major epigenetic regulatory pathway during reproduction and seed development.