Asymmetric inheritance of epigenetic states in asymmetrically dividing stem cells

Asymmetric cell division produces two cells that are genetically identical but each have distinctly different cell fates. During this process, epigenetic mechanisms play an important role in allowing the two daughter cells to have unique gene expression profiles that lead to their specific cell identities. Although the process of duplicating and segregating the genetic information during the cell cycle has been well studied, the question of how epigenetic information is duplicated and partitioned still remains. In this review, we discuss recent advances in understanding how epigenetic states are established and inherited, with emphasis on the asymmetric inheritance patterns of histones, DNA methylation, nonhistone proteins, RNAs, and organelles. We also discuss how misregulation of these processes may lead to diseases such as cancer and tissue degeneration.     

Life as physics and chemistry: A system view of biology

Cellular life can be viewed as one of many physical natural systems that extract free energy from their environments in the most efficient way, according to fundamental physical laws, and grow until limited by inherent physical constraints. Thus, it can be inferred that it is the efficiency of this process that natural selection acts upon. The consequent emphasis on metabolism, rather than replication, points to a metabolism-first origin of life with the adoption of DNA template replication as a second stage development. This order of events implies a cellular regulatory system that pre-dates the involvement of DNA and might, therefore, be based on the information acquired as peptides fold into proteins, rather than on genetic regulatory networks. Such an epigenetic cell regulatory model, the independent attractor model, has already been proposed to explain the phenomenon of radiation induced genomic instability. Here it is extended to provide an epigenetic basis for the morphological and functional diversity that evolution has yielded, based on natural selection of the most efficient free energy transduction. Empirical evidence which challenges the current genetic basis of cell and molecular biology and which supports the above proposal is discussed.     

生殖细胞形成的调控机制及体外培养体系的研究进展

生殖细胞是多细胞生物体遗传物质传递的载体,在发育生物学、临床医学及畜牧业生产等领域中具有广阔的应用前景。原始生殖细胞作为胚胎体内最早出现的生殖细胞,在发育过程中受多种信号因子的诱导,发生特化、迁移、分化及减数分裂,最终形成单倍体的配子,此过程在遗传学和表观遗传学方面受到严格的调控。另外,多能性干细胞向生殖细胞的分化以及生殖细胞的体外培养方面在最近均取得了较大的进展。该文将主要围绕原始生殖细胞,综述最近几年来关于生殖细胞形成中的转录调控及体外培养体系的进展。     

Resistance of cultured human fibroblasts and other cells to purine and pyrimidine analogues in relation to mutagenesis detection

In vitro enumeration of diploid human cell variants that are resistant to purine analogues is a possible method of detecting mutagenesis. Their incidences can be increased by the known mutagens, X-rays and N-methyl-N′-nitro-N-nitrosoguanidine (MNNG). Usefulness of this method depends on the kinds of hereditary changes that confer analogue-resistance on somatic cells. If resistance usually results from changes in genetic material, in vitro studies could be useful indicators of mutagenic effects on somatic cells and germ cells in vivo. If epigenetic changes are primarily responsible for analogue-resistant variants, their enumeration might not provide information relevant to germinal mutations but would still be a useful way to detect induction of general kinds of stable phenotypic changes that could cause cancer. This article outlines hypothetical epigenetic and genetic causes of somatic cell variation and a prospective genetic analysis of human cell variants that are resistant to 8-azaguanine (AG) or 2,6-diaminopurine ( (DAP).Recent evidences and arguments favoring epigenetic origins of resistance to base-analogues are inconclusive. The often cited high rate of changes causing impermeability to BUdR in hamster cells is based on one improperly executed determination. Comparisons of rates of variation conferring BUdR-resistance on cultured haploid and diploid frog cells included diploid variants that did not behave as mutants and ignored major sources of error in estimating mutation rates. AG-resistance could result from recessive mutations in X-chromosomal genes but comparisons of rates of mutation in hamster cells of different ploidies did not provide information about the numbers of X-chromosomes in the variants. Reports that normal rodent HGPRT reappeared in hybrids of enzyme-deficient rodent cells and HGPRT-containing cells of other species or in the rodent cells alone in response to the conditions of cell hybridization did not include adequate controls for reversions in mutant genes of the rodent cells. Questions about the epigenetic and genetic origins of analogue-resistance are mostly unanswered. It remains possible that some kinds of abnormal epigenetic changes cause somatic disease. Specific methods for detecting their occurrence and responsiveness to environmental factors should be devised by focusing efforts on traits that are normally subject to epigenetic regulation. Derepression of genes on the inactive X-chromosome and of liver phenylalanine hydroxylase production are presented as possible examples of abnormal epigenetic changes that could be quantitatively studied by direct selection in vitro.     

Towards an understanding of the epigenetics of schistosomes: a comparative epigenomic study

As in perhaps all eukaryotes, schistosomes use a supplementary information transmitting system, the epigenetic inheritance system, to shape genetic information and to produce different phenotypes. In contrast to other important parasites, the study of epigenetic phenomena in schistosomes is still in its infancy. Nevertheless, we are beginning to grasp what goes on behind the epigenetic scene in this parasite. We have developed techniques of native chromatin immunoprecipitation (N-ChIP) and associated the necessary bioinformatics tools that allow us to run genome-wide comparative chromatin studies on Schistosoma mansoni at different stages of its life cycle, on different strains and on different sexes. We present here an application of such an approach to study the genetic and epigenetic basis for a phenotypic trait, the compatibility of S. mansoni with its invertebrate host Biomphalaria glabrata. We have applied the ChIP procedure to two strains that are either compatible or incompatible with their intermediate host. The precipitated DNA was sequenced and aligned to a reference genome and this information was used to determine regions in which both strands differ in their genomic sequence and/or chromatin structure. This procedure allowed us to identify candidate genes that display either genetic or epigenetic difference between the two strains.     

Natural epigenetic variation in plant species: a view from the field

Researchers are beginning to use wild plant populations to survey and assess cytosine methylation polymorphisms in a population and ecological genetic framework. These studies support the plausibility of adaptive epigenetic alleles, but uncertainty remains due to the difficulty in untangling genetic and epigenetic variation in wild populations. The increasing emphasis on stress-induced epigenetic alterations and transgenerational phenomena among researchers focused on epigenetic mechanisms should push practitioners of this subfield to consider the questions and tools of colleagues grappling with epigenetics from ecological and evolutionary perspectives.     

The Developmental Basis of Identity

We are each the product of our development. The nature of the developmental process by which each of us was formed is described from gametogenesis to neonatality. The varied influences upon that process and their relative balance and patterns of interaction are then considered. In particular, the relative importance of epigenetic and genetic factors is discussed. It is concluded that development is a continuous process involving epigenetic/genetic interactions throughout. The contemporary emphasis on the genetic basis for human individuality is reviewed critically.     

Beyond regulations at DNA levels: A review of epigenetic therapeutics targeting cancer stem cells

In the past few years, the paramount role of cancer stem cells (CSCs), in terms of cancer initiation, proliferation, metastasis, invasion and chemoresistance, has been revealed by accumulating studies. However, this level of cellular plasticity cannot be entirely explained by genetic mutations. Research on epigenetic modifications as a complementary explanation for the properties of CSCs has been increasing over the past several years. Notably, therapeutic strategies are currently being developed in an effort to reverse aberrant epigenetic alterations using specific chemical inhibitors. In this review, we summarize the current understanding of CSCs and their role in cancer progression, and provide an overview of epigenetic alterations seen in CSCs. Importantly, we focus on primary cancer therapies that target the epigenetic modification of CSCs by the use of specific chemical inhibitors, such as histone deacetylase (HDAC) inhibitors, DNA methyltransferase (DNMT) inhibitors and microRNA‐based (miRNA‐based) therapeutics.     

Histone modifications as a platform for cancer therapy

Tumorigenesis and metastasis are a progression of events resulting from alterations in the processing of the genetic information. These alterations result from stable genetic changes (mutations) involving tumor suppressor genes and oncogenes (e.g., ras, BRAF) and potentially reversible epigenetic changes, which are modifications in gene function without a change in the DNA sequence. Mutations of genes coding for proteins that directly or indirectly influence epigenetic processes will alter the cell's gene expression program. Epigenetic mechanisms often altered in cancer cells are DNA methylation and histone modifications (acetylation, methylation, phosphorylation). This article will review the potential of these reversible epigenetic processes as targets for cancer therapies.     

Reconstitution of Gametogenesis In Vitro:Meiosis Is the Biggest Obstacle

Germ-line cells are responsible for transmitting genetic and epigenetic information across generations, and ensuring the creation of new individuals from one generation to the next. Gametogenesis process requires several rigorous steps, including primordial germ cell （PGC） specification, proliferation, migration to the gonadal ridges and differentiation into mature gametes such as sperms and oocytes. But this process is not clearly explored because a small number of PGCs are deeply embedded in the developing embryo. In the attempt to establish an in vitro model for understanding gametogenesis process well, several groups have made considerable progress in differen- tiating embryonic stem cells （ESCs） and adult stem cells （ASCs） into germ-like cells over the past ten years. These stem cell-derived germ cells appear to he capable of undergoing meiosis and generating both male and female gametes. But most of gametes turn out to be not fully functional due to their abnormal meiosis process compared to endogenous germ cells. Therefore, a robust system of differentiating stem cells into germ cells would enable us to investigate the genetic, epigenetic and environmental factors associated with germ cell development. Here, we review the stem cell-derived germ cell development, and discuss the potential and challenges in the differentiation of functional germ cells from stem cells.     

Single-molecule imaging of epigenetic complexes in living cells: insights from studies on Polycomb group proteins

Chromatin-associated factors must locate, bind to, and assemble on specific chromatin regions to execute chromatin-templated functions. These dynamic processes are essential for understanding how chromatin achieves regulation, but direct quantification in living mammalian cells remains challenging. Over the last few years, live-cell single-molecule tracking (SMT) has emerged as a new way to observe trajectories of individual chromatin-associated factors in living mammalian cells, providing new perspectives on chromatin-templated activities. Here, we discuss the relative merits of live-cell SMT techniques currently in use. We provide new insights into how Polycomb group (PcG) proteins, master regulators of development and cell differentiation, decipher genetic and epigenetic information to achieve binding stability and highlight that Polycomb condensates facilitate target-search efficiency. We provide perspectives on liquid-liquid phase separation in organizing Polycomb targets. We suggest that epigenetic complexes integrate genetic and epigenetic information for target binding and localization and achieve target-search efficiency through nuclear organization.     

Epigenetic stability of embryonic stem cells and developmental potential

Recent studies highlight the tremendous potential of human embryonic stem (ES) cells and their derivatives as therapeutic tools for degenerative diseases. However, derivation and culture of ES cells can induce epigenetic alterations, which can have long lasting effects on gene expression and phenotype. Research on human and mouse stem cells indicates that developmental, cancer-related genes, and genes regulated by genomic imprinting are particularly susceptible to changes in DNA methylation. Together with the occurrence of genetic alterations, epigenetic instability needs to be monitored when considering human stem cells for therapeutic and technological purposes. Here, we discuss the maintenance of epigenetic information in cultured stem cells and embryos and how this influences their developmental potential.     

Cause and Consequences of Genetic and Epigenetic Alterations in Human Cancer

Both genetic and epigenetic changes contribute to development of human cancer. Oncogenomics has primarily focused on understanding the genetic basis of neoplasia, with less emphasis being placed on the role of epigenetics in tumourigenesis. Genomic alterations in cancer vary between the different types and stages, tissues and individuals. Moreover, genomic change ranges from single nucleotide mutations to gross chromosomal aneuploidy; which may or may not be associated with underlying genomic instability. Collectively, genomic alterations result in widespread deregulation of gene expression profiles and the disruption of signalling networks that control proliferation and cellular functions. In addition to changes in DNA and chromosomes, it has become evident that oncogenomic processes can be profoundly influenced by epigenetic mechanisms. DNA methylation is one of the key epigenetic factors involved in regulation of gene expression and genomic stability, and is biologically necessary for the maintenance of many cellular functions. While there has been considerable progress in understanding the impact of genetic and epigenetic mechanisms in tumourigenesis, there has been little consideration of the importance of the interplay between these two processes. In this review we summarize current understanding of the role of genetic and epigenetic alterations in human cancer. In addition we consider the associated interactions of genetic and epigenetic processes in tumour onset and progression. Furthermore, we provide a model of tumourigenesis that addresses the combined impact of both epigenetic and genetic alterations in cancer cells.     

The Epigenetic Switches for Neural Development and Psychiatric Disorders

The most remarkable feature of the nervous system is that the development and functions of the brain are largely reshaped by postnatal experiences, in joint with genetic landscapes. The nature vs. nurture argument reminds us that both genetic and epigenetic information is indispensable for the normal function of the brain. The epigenetic regulatory mechanisms in the central nervous system have been revealed over last a decade. Moreover, the mutations of epigenetic modulator genes have been shown to be implicated in neuropsychiatric disorders, such as autism spectrum disorders. The epigenetic study has initiated in the neuroscience field for a relative short period of time. In this review, we will summarize recent discoveries about epigenetic regulation on neural development, synaptic plasticity, learning and memory, as well as neuropsychiatric disorders. Although the comprehensive view of how epigenetic regulation contributes to the function of the brain is still not completed, the notion that brain, the most complicated organ of organisms, is profoundly shaped by epigenetic switches is widely accepted.     

The frame of non-canonical theory of heredity: from genes to epigenes

Particular theory of heredity that exceeds the limits of mendelian genetics is suggested. The model based on five sufficiently obvious assumptions (accepted as axioms) As consequence of these axioms the strict statements concerningfunctional heredity memory were formulated in mathematical terms. Molecular-genetic realization of the memory cells appears as new class of heredity units--epigenes. In the epigenes part f hereditary information is contained, encoded and transmitted beyond the primary structure of DNA molecules of genome. Epigenes capable to conserve sequences of genes functional states in the course of ontogenesis and provide transmission of information contained in this states throw consequent generations. It was shown that epigenes differ from genes at least by encoding method of heredity information. There are three functional-equivalent classes of really existing epigenes mechanisms: dynamic, modificational and transpositional; and there is one hypothetical class--invertional. It was shown that a lot of experimental data concerning epigenetic mechanism of heredity is in accord with theoretical conclusions concerning epigenes existence. Moreover, we constructed an artificial epigenes by genetic engineering methods. The existence of epigenes means that obtaining complete genome sequence, its physical and genetic maps, as well as distinguishing the rules of genes function encoding by its primary structure do not provide complete decoding of hereditary information. The role of epigenes in ontogenesis and phylogenesis was examined. It was shown that even elementary epigenetic systems could determine key ontogenesis events. Epigenetic system could serve as the basis of non-darwinian evolutionary strategies by means of "memorization of rather unsuccessfully steps of evolution" and conservation of alternative variants of ontogenesis. Teleonomic hypothesis on functional heredity memory was formulated. This theory provides explanation of phenomena of acquired features inheritance and molecular mechanisms of stress-induced evolution.     

Histone variants meet their match

A fascinating aspect of how chromatin structure impacts on gene expression and cellular identity is the transmission of information from mother to daughter cells, independently of the primary DNA sequence. This epigenetic information seems to be contained within the covalent modifications of histone polypeptides and the distinctive characteristics of variant histone subspecies. There are specific deposition pathways for some histone variants, which provide invaluable mechanistic insights into processes whereby the major histones are exchanged for their more specialized counterparts.