Information about a form (on the dynamic laws of morphogenesis)

How a developing embryo becomes "informed" about its form?" This problem remains obscure and controversial. We argue that the "information about a form" is distributed throughout three main components: the dynamic laws, the parameters and the initial/boundary conditions. In the absence of a dynamic law two other components are "blind", that is, do not contain any unambiguous information. We present a version of a dynamic law of morphogenesis, based upon the presumption of a feedback between passive and active mechanical stresses. We explore several models of shape formation based upon this law and show that, as depending upon the parameters values, they generate a large set of realistic shapes. Genetic and epigenetic basis of the models parameters is discussed.     

Biological pathways to adaptability--interactions between genome, epigenome, nervous system and environment for adaptive behavior

Because living systems depend on their environment, the evolution of environmental adaptability is inseparable from the evolution of life itself (Pross 2003). In animals and humans, environmental adaptability extends further to adaptive behavior. It has recently emerged that individual adaptability depends on the interaction of adaptation mechanisms at diverse functional levels. This interaction enables the integration of genetic, epigenetic and environmental factors for coordinated regulation of adaptations. In this review, we first present the basis for the regulation of adaptation mechanisms across functional levels. We then focus on neuronal activity-regulated adaptation mechanisms that involve the regulation of genes, noncoding DNA (ncDNA), ncRNAs and proteins to change the structural and functional properties of neurons. Finally, we discuss a selection of these important neuronal activity-regulated molecules and their effects on brain structure and function and on behavior. Most of the evidence so far is based on sampling of animal tissue or post-mortem studies in humans. However, we also present techniques that combine genetic with behavioral and neurophysiological measures in humans (e.g. genetic imaging) and discuss their potential and limitations. We argue that we need to understand how neuronal activity-dependent adaptation mechanisms integrate genetic, epigenetic and experience-dependent signals in order to explain individual variations in behavior and cognitive performance.     

Potential of DNMT and its Epigenetic Regulation for Lung Cancer Therapy

Lung cancer, the leading cause of mortality in both men and women in the United States, is largely diagnosed at its advanced stages that there are no effective therapeutic alternatives. Although tobacco smoking is the well established cause of lung cancer, the underlying mechanism for lung tumorigenesis remains poorly understood. An important event in tumor development appears to be the epigenetic alterations, especially the change of DNA methylation patterns, which induce the most tumor suppressor gene silence. In one scenario, DNA methyltransferase (DNMT) that is responsible for DNA methylation accounts for the major epigenetic maintenance and alternation. In another scenario, DNMT itself is regulated by the environment carcinogens (smoke), epigenetic and genetic information. DNMT not only plays a pivotal role in lung tumorigenesis, but also is a promising molecular bio-marker for early lung cancer diagnosis and therapy. Therefore the elucidation of the DNMT and its related epigenetic regulation in lung cancer is of great importance, which may expedite the overcome of lung cancer.Key Words: Lung cancer, epigenetic regulation, DNA methylation, DNMT, gene silence, epigenetic therapy.     

Epigenetics and cancer

Epigenetics is defined as "the study of mitotically and/or meiotically heritable changes in gene expression that cannot be explained by changes in the DNA sequence". Setting up the epigenetic program is crucial for correct development and its stable inheritance throughout its lifespan is essential for the maintenance of the tissue- and cell-specific functions of the organism. For many years, the genetic causes of cancer have hold centre stage. However, the recent wealth of information about the molecular mechanisms which, by modulating the chromatin structure, can regulate gene expression has high-lighted the predominant role of epigenetic modifications in the initiation and progression of numerous pathologies, including cancer. The nucleosome is the major target of these epigenetic regulation mechanisms. They include a series of tightly interconnected steps which starting with the setting ("writing") of the epigenetic mark till its "reading" and interpretation will result in long-term gene regulation. The major epigenetic changes associated with tumorigenesis are aberrant DNA methylation of CpG islands located in the promoter region of tumor suppressor gene, global genomic hypomethylation and covalent modifications of histone N-terminal tails which are protruding out from the nucleosome core. In sharp contrast with genetic modifications, epigenetic modifications are highly dynamic and reversible. The characterization of specific inhibitors directed against some key epigenetic players has opened a new and promising therapeutic avenue, the epigenetic therapy, since some inhibitors are already used in clinical trials.     

Mechanical aspects of cardiac development

Heart development depends on a dynamic interaction between genetic and epigenetic factors. This paper discusses some of the biomechanical processes that help shape the heart in the embryo. First, an overview is given of some of the critical events that occur during cardiac development. Next, mechanics and modeling strategies are discussed for the morphogenetic processes of cardiac tube formation, cardiac looping, myocardial trabeculation, septation, valve formation, and muscle-fiber alignment. Finally, some considerations for future work in this area are listed.     

表遗传学推动新一轮遗传学的发展

科学的发展孕育着突破,表遗传学研究推动着新一轮的遗传学的发展。表遗传学是研究没有DNA序列变化的、可遗传的表达改变。表遗传学不仅对医学和农业有重要的实践意义,而且还提供了理解遗传和进化的新观点。研究表明,人类基因组含有两类遗传信息,遗传学信息提供了合成生命所必需蛋白质的模板,而表遗传学信息提供了何时、何地和怎样地应用遗传学信息的指令;遗传学和表遗传学的关系有如“阴阳”,它们既相区别又协同参与调节生命活动。同时还讨论了基因的概念、进化和epigenetics的中文译名等问题。表遗传学研究应引起国内学术界的关注。Abstract: Scientific development is pregnant with a breakthrough, epigenetic studies are pushing the genetics forward. Epigenetics is the study of heritable changes in gene expression that occurs without a change in DNA sequence. Epigenetics not only has practical significance for medicine and agriculture, but also provides new views on understanding heredity and evolution. Human genome contains information in two forms: the genetic information provides the blueprint for the manufacture of all the proteins necessary to create a living thing while the epigenetic information provides instructions on how, where, and when the genetic information should be used. The interrelationship of genetics and epigenetics is like a yin-yan, they are different from each other, and cooperatively take part in regulation of a variety of living activities. In this paper concept of gene and problems of evolution has been also discussed according to epigenetic viewpoints.     

Master and servant: epigenetic deregulations as a cause and a consequence of cancer

The processes that affect the activity of the genome in a heritable manner without changing its sequence are called epigenetic. Here we review the modes of epigenetic gene regulation, and describe their alterations in cancer. We show how these mechanisms are interdependent, and how they intersect with genetic mutations. We argue that epigenetic abnormalities can occur both as a cause, and as a consequence of cancer. Indeed, oncogenic transformation can deeply alter the epigenetic information contained in the pattern of DNA methylation or histone tail modification. Conversely, epigenetic dysfunctions can drive cellular transformation. We then touch on some practical consequences of the prominence of epigenetic alterations in cancer : increasing knowledge of this field has allowed the development of a new generation of diagnostic tools and therapeutic avenues. Finally we point out that epigenetic phenomena may act as sensors that link environmental conditions to cancer.     

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.     

An integrated epigenetic and genetic approach to common human disease

Epigenetic information is heritable during cell division but is not contained within the DNA sequence itself. Despite increasing evidence for and interest in the role of epigenetics in human disease, particularly in cancer, virtually no epigenetic information is routinely or systematically measured at the genome level. The current population-based approach to common disease relates common DNA sequence variants to either disease status or incremental quantitative traits contributing to disease. Although this purely genetic approach is powerful and general, there is currently no conceptual framework to integrate epigenetic information. In this article, we propose an approach to common human disease that incorporates epigenetic variation into genetic studies. Epigenetic variation might also help to explain the late onset and progressive nature of most common diseases, the quantitative nature of complex traits and the role of environment in disease development, which a purely sequence-based approach might not.     

On the cause and mechanism of phenoptosis

Based upon evolvability theory, phenotypes like aging that offer no apparent individual benefit may evolve nonetheless. Pursuant to that concept, the evolution of a hypothetical, genome-based aging program called phenoptosis was proposed. However, while aging may facilitate evolvability, it need not result from a program specifically selected for that purpose. Instead, it is possible that the potential for aging is conserved within the genome as a part of a beneficial program that orchestrates and integrates developmental transformation of the soma from conception to maturation. Because somatic remodeling is inherently unstable, its continued non-programmatic expression beyond young adulthood (developmental inertia) erodes internal order, initiating and exacerbating aging. Thus, aging may result paradoxically from post-maturational expression of the same programmatic function for somatic transformation that previously provided individual benefit. It did so by ensuring acquisition of reproductive competence, post-reproductive development of parents to nurture offspring and thereby, to guarantee species survival. In an attempt to identify genes capable of controlling developmental inertia, we sequenced DNA from a series of subjects displaying extreme neoteny, i.e. retention of youthful characteristics during adulthood. We hoped to identify mutations associated with delayed development and to compare each subject’s biological and chronological ages. De novo mutations of coding-genes were found in all the subjects, but they could not be definitively identified as a cause of developmental delay. Nonetheless, genetic and epigenetic studies of neotenic subject’s DNA are on-going. We are attempting to determine if phenoptosis specifically evolved to cause aging, or rather if it exists as a cryptic component of the developmental program that expresses its lethal potential serendipitously and only after individual benefit is realized.     

The cellular computer DNA: Program or data

The classical metaphor of the genetic program written in the DNA nucleotidic sequences is reconsidered. Recent works on algorithmic complexity and logical properties of computer programs and data are used to question the explanatory value of that metaphor. Structural properties of strings are looked for which would be necessary to apply to DNA sequences if the metaphor is to be taken literally. The notion of sophistication is used to quantify meaningful complexity and to distinguish it from classical computational complexity. In this context, the distinction between program and data becomes relevant and an alternative metaphor of DNA as data to a parallel computing network embedded in the global geometrical and biochemical structure of the cell is discussed. An intermediate picture of an evolving network emerges as the most likely where the output of the cellular computing network can produce, at a different time scale, changes in the structure of the network itself by means of changes in the DNA activity patterns.     

Longitudinal,genome-scale analysis of DNA methylation in twins from birth to 18 months of age reveals rapid epigenetic change in early life and pair-specific effects of discordance

Background

The extent to which development- and age-associated epigenetic changes are influenced by genetic, environmental and stochastic factors remains to be discovered. Twins provide an ideal model with which to investigate these influences but previous cross-sectional twin studies provide contradictory evidence of within-pair epigenetic drift over time. Longitudinal twin studies can potentially address this discrepancy.

Results

In a pilot, genome-scale study of DNA from buccal epithelium, a relatively homogeneous tissue, we show that one-third of the CpGs assayed show dynamic methylation between birth and 18 months. Although all classes of annotated genomic regions assessed show an increase in DNA methylation over time, probes located in intragenic regions, enhancers and low-density CpG promoters are significantly over-represented, while CpG islands and high-CpG density promoters are depleted among the most dynamic probes. Comparison of co-twins demonstrated that within-pair drift in DNA methylation in our cohort is specific to a subset of pairs, who show more differences at 18 months. The rest of the pairs show either minimal change in methylation discordance, or more similar, converging methylation profiles at 18 months. As with age-associated regions, sites that change in their level of within-pair discordance between birth and 18 months are enriched in genes involved in development, but the average magnitude of change is smaller than for longitudinal change.

Conclusions

Our findings suggest that DNA methylation in buccal epithelium is influenced by non-shared stochastic and environmental factors that could reflect a degree of epigenetic plasticity within an otherwise constrained developmental program.     

Epigenetics and airways disease

Epigenetics is the term used to describe heritable changes in gene expression that are not coded in the DNA sequence itself but by post-translational modifications in DNA and histone proteins. These modifications include histone acetylation, methylation, ubiquitination, sumoylation and phosphorylation. Epigenetic regulation is not only critical for generating diversity of cell types during mammalian development, but it is also important for maintaining the stability and integrity of the expression profiles of different cell types. Until recently, the study of human disease has focused on genetic mechanisms rather than on non-coding events. However, it is becoming increasingly clear that disruption of epigenetic processes can lead to several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. Furthermore, the expression and activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in the airways of patients with respiratory disease. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. These changes, despite being heritable and stably maintained, are also potentially reversible and there is scope for the development of 'epigenetic therapies' for disease.     

Epigenetic drugs as pleiotropic agents in cancer treatment: biomolecular aspects and clinical applications

In the last three decades huge efforts have been made to characterize genetic defects responsible for cancer development and progression, leading to the comprehensive identification of distinct cellular pathways affected by the alteration of specific genes. Despite the undoubtable role of genetic mechanisms in triggering neoplastic cell transformation, epigenetic modifications (i.e., heritable changes of gene expression that do not derive from alterations of the nucleotide sequence of DNA) are rapidly emerging as frequent alterations that often occur in the early phases of tumorigenesis and that play an important role in tumor development and progression. Epigenetic alterations, such as modifications in DNA methylation patterns and post-translational modifications of histone tails, behave extremely different from genetic modifications, being readily revertable by "epigenetic drugs" such as inhibitors of DNA methyl transferases and inhibitors of histone deacetylases. Since epigenetic alterations in cancer cells affect virtually all cellular pathways that have been associated to tumorigenesis, it is not surprising that epigenetic drugs display pleiotropic activities, being able to concomitantly restore the defective expression of genes involved in cell cycle control, apoptosis, cell signaling, tumor cell invasion and metastasis, angiogenesis and immune recognition. Prompted by this emerging clinical relevance of epigenetic drugs, this review will focus on the large amount of available data, deriving both from in vitro experimentations and in vivo pre-clinical and clinical studies, which clearly indicate epigenetic drugs as effective modifiers of cancer phenotype and as positive regulators of tumor cell biology with a relevant therapeutic potential in cancer patients.     

The plant genome's methylation status and response to stress: implications for plant improvement

Plant improvement depends on generating phenotypic variation and selecting for characteristics that are heritable. Classical genetics and early molecular genetics studies on single genes showed that differences in chromatin structure, especially cytosine methylation, can contribute to heritable phenotypic variation. Recent molecular genetic and genomic studies have revealed a new importance of cytosine methylation for gene regulation and have identified RNA interference (RNAi)-related proteins that are necessary for methylation. Methylation differences among plants can be caused by cis- or trans-acting DNA polymorphisms or by epigenetic phenomena. Although regulatory proteins might be important in creating this variation, recent examples highlight the central role of transposable elements and DNA repeats in generating both genetic and epigenetic methylation polymorphisms. The plant genome's response to environmental and genetic stress generates both novel genetic and epigenetic methylation polymorphisms. Novel, stress-induced genotypes may contribute to phenotypic diversity and plant improvement.     

Stable loss of global DNA methylation in the radiation-target tissue--a possible mechanism contributing to radiation carcinogenesis?

Radiation-induced lymphomagenesis and leukemogenesis are complex processes involving both genetic and epigenetic changes. Although genetic alterations during radiation-induced lymphoma- and leukemogenesis are fairly well studied, the role of epigenetic changes has been largely overlooked. Rodent models are valuable tools for identifying molecular mechanisms of lymphoma and leukemogenesis. A widely used mouse model of radiation-induced thymic lymphoma is characterized by a lengthy "pre-lymphoma" period. Delineating molecular changes occurring during the pre-lymphoma period is crucial for understanding the mechanisms of radiation-induced leukemia/lymphoma development. In the present study, we investigated the role of radiation-induced DNA methylation changes in the radiation carcinogenesis target organ--thymus, and non-target organ--muscle. This study is the first report on the radiation-induced epigenetic changes in radiation-target murine thymus during the pre-lymphoma period. We have demonstrated that acute and fractionated whole-body irradiation significantly altered DNA methylation pattern in murine thymus leading to a massive loss of global DNA methylation. We have also observed that irradiation led to increased levels of DNA strand breaks 6 h following the initial exposure. The majority of radiation-induced DNA strand breaks were repaired 1 month after exposure. DNA methylation changes, though, were persistent and significant radiation-induced DNA hypomethylation was observed in thymus 1 month after exposure. In sharp contrast to thymus, no significant persistent changes were noted in the non-target muscle tissue. The presence of stable DNA hypomethylation in the radiation-target tissue, even though DNA damage resulting from initial genotoxic radiation insult was repaired, suggests of the importance of epigenetic mechanisms in the development of radiation-related pathologies. The possible role of radiation-induced DNA hypomethylation in radiation-induced genome instability and aberrant gene expression in molecular etiology of thymic lymphomas is discussed.     

表观遗传调控在糖尿病及其并发症中的作用

表观遗传(epigenetics)是指DNA序列不发生变化但基因表达却发生了可遗传的改变．表观遗传调控过程十分复杂,主要包括DNA甲基化、组蛋白修饰和微小RNA(miRNA)等．糖尿病是一种慢性代谢性疾病,常伴随大血管和微血管并发症．糖尿病的发生、发展不仅取决于遗传因素,而且也受到表观遗传修饰的调控．因此,对表观遗传调控的研究将为糖尿病及其并发症的预防和治疗提供新的思路和方法．     

DNA methylation profiling in cancer: from single nucleotides towards methylome

Genomic DNA methylation pattern (methylome) represents epigenetic program of a cell. It controls expression of genetic information. In tumor cells, significant alterations in DNA methylation take place, which can be identified as one of the earliest and most consistent features of tumorigenesis. Detailed survey of methylcytosines' distribution in genome is extremely important for understanding of real tumor etiology and early diagnostics. Progress in the field has been hampered by the unavailability of methods for large-scale determination of methylation patterns. Nowadays, variety of techniques is in development that allow for highly parallel regime of samples analysis (high-throughput analysis) or large loci DNA profiling (large-scale analysis). Aim of the work is to consider the main trends in the field of new methods development. The principles of the most frequently used approaches to DNA methylation studies are reviewed as well as their application and results. Most attention is paid to DNA microarrays as a technology of choice for epigenetic tumor analysis (oligonucleotide microarrays, BAC-arrays etc.). Alternative DNA sequencing based techniques are discussed, which can soon take on the leadership. Results of a large-scale analysis can be used for identification of new epigenetic markers and epigenetic classification of neoplasia.