<Emphasis Type="Bold">Epigenetic variation in clonal stands of aspen</Emphasis>

Epigenetic mechanisms can affect ecologically important traits, even in the absence of genetic variation. Environmental factors can influence gene regulation through chemical modifications, such as DNA methylation, resulting in acclimation that can be transferred to subsequent cell generations both mitotically and meiotically. Clonal plants such as Populus tremuloides (aspen) show considerable promise as model species for the long-term in situ study of ecological epigenetics. The common replication of identical genotypes across heterogeneous environments permits within- and between-genotype comparisons while controlling for genetic makeup. With a long lifespan and limited natural selection resulting from sexual recombination, it is conceivable that epigenetic acclimation plays an important role in the long-term ecological success of aspen. This case study is the first in a series investigating the role of epigenetics in aspen ecology. We have established long-term permanent plots of aspen, identified (genotyped) clones and established the baseline epigenetic structure. Here we report the in situ epigenetic structure of two aspen stands. We find considerable epigenetic variation and significant differences within and among genotypes and sites, suggesting both genotype and environment influence the epigenotype.     

Spatiotemporal dynamics of regulatory protein recruitment at DNA damage sites

Mammalian cells are constantly threatened by multiple types of DNA lesions arising from various sources like irradiation, environmental agents, replication errors or by-products of the normal cellular metabolism. If not readily detected and repaired these lesions can lead to cell death or to the transformation of cells giving rise to life-threatening diseases like cancer. Multiple specialized repair pathways have evolved to preserve the genetic integrity of a cell. The increasing number of DNA damage sensors, checkpoint regulators, and repair factors identified in the numerous interconnected repair pathways raises the question of how DNA repair is coordinated. In the last decade, various methods have been developed that allow the induction of DNA lesions and subsequent real-time analysis of repair factor assembly at DNA repair sites in living cells. This combination of biophysical and molecular cell biology methods has yielded interesting new insights into the order and kinetics of protein recruitment and identified regulatory sequences and selective loading platforms for the efficient restoration of the genetic and epigenetic integrity of mammalian cells.     

Roles of chromatin assembly factor 1 in the epigenetic control of chromatin plasticity

Genetic information embedded in DNA sequence and the epigenetic information marked by modifications on DNA and histones are essential for the life of eukaryotes. Cells have evolved mechanisms of DNA duplication and chromatin restoration to ensure the inheritance of genetic and epigenetic information during cell division and development. In this review, we focus on the maintenance of epigenetic landscape during chromatin dynamics which requires the orchestration of histones and their chaperones. We discuss how epigenetic marks are re-established in the assembly of new chromatin after DNA replication and repair, highlighting the roles of CAF-1 in the process of changing chromatin state. The functions of CAF-1 provide a link between chromatin assembly and epigenetic restoration.     

Genome‐wide signature of local adaptation linked to variable CpG methylation in oak populations

It has long been known that adaptive evolution can occur through genetic mutations in DNA sequence, but it is unclear whether adaptive evolution can occur through analogous epigenetic mechanisms, such as through DNA methylation. If epigenetic variation contributes directly to evolution, species under threat of disease, invasive competition, climate change or other stresses would have greater stores of variation from which to draw. We looked for evidence of natural selection acting on variably methylated DNA sites using population genomic analysis across three climatologically distinct populations of valley oaks. We found patterns of genetic and epigenetic differentiations that indicate local adaptation is operating on large portions of the oak genome. While CHG methyl polymorphisms are not playing a significant role and would make poor targets for natural selection, our findings suggest that CpG methyl polymorphisms as a whole are involved in local adaptation, either directly or through linkage to regions under selection.     

The minimal genome paradox

The concept of a 'minimal genome' has appeared as an attempt to answer the question what the minimum number of genes or minimum amount of DNA to support life is. Since bacteria are cells bearing the smallest genomes, it has been generally accepted that the minimal genome must belong to a bacterial species. Currently the most popular chromosome in studies on a minimal genome belongs to Mycoplasma genitalium, a parasite bacterium whose total genetic material is as small as approximately 580 kb. However, the problem is how we define life, and thus also a minimal genome. M. genitalium is a parasite and requires substances provided by its host. Therefore, if a genome of a parasite can be considered as a minimal genome, why not to consider genomes of bacteriophages? Going further, bacterial plasmids could be considered as minimal genomes. The smallest known DNA region playing the function of the origin of replication, which is sufficient for plasmid survival in natural habitats, is as short as 32 base pairs. However, such a small DNA molecule could not form a circular form and be replicated by cellular enzymes. These facts may lead to an ostensibly paradoxical conclusion that the size of a minimal genome is restricted by the physical size of a DNA molecule able to replicate rather, than by the amount of genetic information.     

The replicon revisited: an old model learns new tricks in metazoan chromosomes

The origins of DNA replication were proposed in the replicon model to be specified genetically by replicator elements that coordinate the initiation of DNA synthesis with gene expression and cell growth. Recent studies have identified DNA sequences in mammalian cells that fulfil the genetic criteria for replicators and are beginning to uncover the sequence requirements for the initiation of DNA replication. Mammalian replicators are com- posed of non-redundant modules that cooperate to direct initiation to specific chromosomal sites. Conversely, replicators do not show strong sequence similarity, and their ability to initiate replication depends on the chromosomal context and epigenetic factors, as well as their primary sequence. Here, we review the properties of metazoan replicators, and discuss the genetic and epigenetic factors that determine where and when DNA replication is initiated.     

Defining the replication program through the chromatin landscape

DNA replication is an essential cell cycle event required for the accurate and timely duplication of the chromosomes. It is essential that the genome is replicated accurately and completely within the confines of S-phase. Failure to completely copy the genome has the potential to result in catastrophic genomic instability. Replication initiates in a coordinated manner from multiple locations, termed origins of replication, distributed across each of the chromosomes. The selection of these origins of replication is a dynamic process responding to both developmental and tissue-specific signals. In this review, we explore the role of the local chromatin environment in regulating the DNA replication program at the level of origin selection and activation. Finally, there is increasing molecular evidence that the DNA replication program itself affects the chromatin landscape, suggesting that DNA replication is critical for both genetic and epigenetic inheritance.     

Environmental carcinogenesis: an integrative model.

An integrative theory is proposed in which environmental carcinogenesis is viewed as a process by which the genetic control of cell division and differentiation is altered by carcinogens. In this theory, carcinogens include physical, chemical, and viral "mutagens," as well as chemical and viral gene modulators. Existing explanations of carcinogenesis can be considered either as somatic mutation theories or as epigenetic theories. Evidence seems to support the hypothesis that both mutations and epigenetic processes are components of carcinogenesis. The mutational basis of cancer is supported by the clonal nature of tumors, the mutagenicity of most carcinogens, high mutation frequencies in cells of cancer-prone human fibroblasts lacking DNA repair enzymes, the correlation of in vitro DNA damage and in vitro mutation and transformation frequencies with in vivo tumorigenesis, age-related incidences of various hereditary tumors, and the correlation between photoreactivation of DNA damage and the biological amelioration of UV-induced neoplasms. Since both mutagens and gene modulators can be carcinogenic it may be that carcinogens affect genes which control cell division. An integration of the mutation and epigenetic theories of cancer with the "two-stage" theory and Comings's general theory of carcinogenesis is proposed. This integrative theory postulates that carcinogens can affect regulatory genes which control a series of "transforming genes." A general hypothesis is advanced that involves a common mechanism of somatic mutagenesis via error-prone repair of DNA damage which links carcinogenesis, teratogenesis, atherosclerosis and aging. Various concepts are presented to provide a framework for evaluating the scientific, medical, and social implications of cancer.     

Biological evolution as an expression of body-plan potentialities.

A growing bulk of recent data from different fields as molecular biology, developmental biology, genetics, paleontology and phylogenetics shows that organisms play a more active role in their evolution than what postulated by the random variation-natural selection paradigm of the neo-Darwinian synthesis. Organisms show during development and morphogenesis autopoietic processes which are related to their body-plan potentialities. These potentialities are expressed through regulatory networks in which a plastic genome participates together with proteins and other substances in an epigenetic space. The epigenetic systems which arise from this interaction may be inherited and then assume a significant role in evolution becoming the source of new acquired characters. The acquisition of new traits through the epigenetic systems is influenced directly by environmental cues. If this process is coherent with the environmental demands it co-operates with natural selection in organism adaptation. An outstanding role in this context may be played by phenotypic plasticity if, as emerges in recent views, it may constitute a general basis for genetic assimilation processes.     

Variation in DNA methylation transmissibility,genetic heterogeneity and fecundity‐related traits in natural populations of the perennial herb Helleborus foetidus

Inferences about the role of epigenetics in plant ecology and evolution are mostly based on studies of cultivated or model plants conducted in artificial environments. Insights from natural populations, however, are essential to evaluate the possible consequences of epigenetic processes in biologically realistic scenarios with genetically and phenotypically heterogeneous populations. Here, we explore associations across individuals between DNA methylation transmissibility (proportion of methylation‐sensitive loci whose methylation status persists unchanged after male gametogenesis), genetic characteristics (assessed with AFLP markers), seed size variability (within‐plant seed mass variance), and realized maternal fecundity (number of recently recruited seedlings), in three populations of the perennial herb Helleborus foetidus along a natural ecological gradient in southeastern Spain. Plants (sporophytes) differed in the fidelity with which DNA methylation was transmitted to descendant pollen (gametophytes). This variation in methylation transmissibility was associated with genetic differences. Four AFLP loci were significantly associated with transmissibility and accounted collectively for ~40% of its sample‐wide variance. Within‐plant variance in seed mass was inversely related to individual transmissibility. The number of seedlings recruited by individual plants was significantly associated with transmissibility. The sign of the relationship varied between populations, which points to environment‐specific, divergent phenotypic selection on epigenetic transmissibility. Results support the view that epigenetic transmissibility is itself a phenotypic trait whose evolution may be driven by natural selection, and suggest that in natural populations epigenetic and genetic variation are two intertwined, rather than independent, evolutionary factors.     

DNA replication components as regulators of epigenetic inheritance—lesson from fission yeast centromere

Genetic information stored in DNA is accurately copied and transferred to subsequent generations through DNA replication. This process is accomplished through the concerted actions of highly conserved DNA replication components. Epigenetic information stored in the form of histone modifications and DNA methylation, constitutes a second layer of regulatory information important for many cellular processes, such as gene expression regulation, chromatin organization, and genome stability. During DNA replication, epigenetic information must also be faithfully transmitted to subsequent generations. How this monumental task is achieved remains poorly understood. In this review, we will discuss recent advances on the role of DNA replication components in the inheritance of epigenetic marks, with a particular focus on epigenetic regulation in fission yeast. Based on these findings, we propose that specific DNA replication components function as key regulators in the replication of epigenetic information across the genome.     

Simulating the temporal modulation of inducible DNA damage response in Escherichia coli

Living organisms make great efforts to maintain their genetic information integrity. However, DNA is vulnerable to many chemical or physical agents. To rescue the cell timely and effectively, the DNA damage response system must be well controlled. Recently, single cell experiments showing that after DNA damage, expression of the key DNA damage response regulatory protein oscillates with time. This phenomenon is observed both in eukaryotic and bacterial cells. We establish a model to simulate the DNA damage response (SOS response) in bacterial cell Escherichia coli. The simulation results are compared to the experimental data. Our simulation results suggest that the modulation observed in the experiment is due to the fluctuation of inducing signal, which is coupled with DNA replication. The inducing signal increases when replication is blocked by DNA damage and decreases when replication resumes.     

Initiation of eukaryotic DNA replication: conservative or liberal?

The mechanism for initiation of eukaryotic DNA replication is highly conserved: the proteins required to initiate replication, the sequence of events leading to initiation, and the regulation of initiation are remarkably similar throughout the eukaryotic kingdom. Nevertheless, there is a liberal attitude when it comes to selecting initiation sites. Differences appear to exist in the composition of replication origins and in the way proteins recognize these origins. In fact, some multicellular eukaryotes (the metazoans) can change the number and locations of initiation sites during animal development, revealing that selection of initiation sites depends on epigenetic as well as genetic parameters. Here we have attempted to summarize our understanding of this process, to identify the similarities and differences between single cell and multicellular eukaryotes, and to examine the extent to which origin recognition proteins and replication origins have been conserved among eukaryotes. Published 2000 Wiley-Liss, Inc.     

Genetic and epigenetic regulation of stress responses in natural plant populations

Plants have developed intricate mechanisms involving gene regulatory systems to adjust to stresses. Phenotypic variation in plants under stress is classically attributed to DNA sequence variants. More recently, it was found that epigenetic modifications - DNA methylation-, chromatin- and small RNA-based mechanisms - can contribute separately or together to phenotypes by regulating gene expression in response to the stress effect. These epigenetic modifications constitute an additional layer of complexity to heritable phenotypic variation and the evolutionary potential of natural plant populations because they can affect fitness. Natural populations can show differences in performance when they are exposed to changes in environmental conditions, partly because of their genetic variation but also because of their epigenetic variation. The line between these two components is blurred because little is known about the contribution of genotypes and epigenotypes to stress tolerance in natural populations. Recent insights in this field have just begun to shed light on the behavior of genetic and epigenetic variation in natural plant populations under biotic and abiotic stresses. This article is part of a Special Issue entitled: Plant gene regulation in response to abiotic stress.     

The bhopalator: a molecular model of the living cell based on the concepts of conformons and dissipative structures

A molecular model of the living cell has been formulated based on a new theory of enzymic catalysis which takes into account the complementary roles of free energy and genetic information. The elementary units of free energy and genetic information that are necessary and sufficient for effectuating molecular mechanisms responsible for the life of the cell are called conformons. Conformons are visualized as a collection of a small number of catalytic residues of enzymes or segments of nucleic acids that are arranged in space and time with appropriate force vectors so as to cause chemical transformations or physical changes of a substrate or a bound ligand. So defined, conformons provide a plausible molecular means to link the genetic information stored in DNA and its ultimate expression, namely networks of coupled intracellular biochemical reactions and physical processes maintained by a continuous dissipation of free energy--dissipative structures of Prigogine. The proposed model of the living cell appears to possess the potential for bridging the gap between molecular biology and the biology of multicellular systems.     

An epigenetic code for DNA damage repair pathways?

Exposure of living cells to intracellular or external mutagens results in DNA damage. Accumulation of DNA damage can lead to serious consequences because of the deleterious mutation rate resulting in genomic instability, cellular senescence, and cell death. To counteract genotoxic stress, cells have developed several strategies to detect defects in DNA structure. The eukaryotic genomic DNA is packaged through histone and nonhistone proteins into a highly condensed structure termed chromatin. Therefore the cellular enzymatic machineries responsible for DNA replication, recombination, and repair must circumvent this natural barrier in order to gain access to the DNA. Several studies have demonstrated that histone/chromatin modifications such as acetylation, methylation, and phosphorylation play crucial roles in DNA repair processes. This review will summarize the recent data that suggest a regulatory role of the epigenetic code in DNA repair processes. We will mainly focus on different covalent reversible modifications of histones as an initial step in early response to DNA damage and subsequent DNA repair. Special focus on a potential epigenetic histone code for these processes will be given in the last section. We also discuss new technologies and strategies to elucidate the putative epigenetic code for each of the DNA repair processes discussed.