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Heritable Changes (heritable + change)
Selected AbstractsUse of a site-specific recombination-based biosensor for detecting bioavailable toluene and related compounds on rootsENVIRONMENTAL MICROBIOLOGY, Issue 4 2003N. Carol Casavant Summary We constructed and characterized a plasmid-based genetic system that reports the expression of a toluene-responsive promoter (PtbuA1) by effecting an irreversible, heritable change in the biosensor cell. Expression of the reporter gene gfp is strongly repressed in the absence of expression from the PtbuA1 promoter, and high level gfp expression in the original cell and its progeny is mediated by the site-specific recombination machinery of bacteriophage P22 to initiate removal of a repressor cassette. The reporter plasmid pTolLHB was functional in two soil saprophytes, Pseudomonas fluorescens A506 and Enterobacter cloacae JL1157, with the efficiency and sensitivity to low toluene concentrations being optimal in P. fluorescens A506. In culture, 80,100% of the A506 (pTolLHB) population expressed gfp following exposure to 0.2 µm toluene for one to three hours. Compared to the response of A506 containing a plasmid-borne PtbuA1 - gfp fusion, the recombination-based biosensor was more sensitive at detecting low toluene and trichloroethylene concentrations. An A506 (pTolLHB) inoculum, which had a background of 2.5% of the cells expressing gfp, was introduced onto barley roots in soil microcosms. If toluene was introduced into the microcosms, after 24 h, 72% of the A506 (pTolLHB) cells recovered from roots expressed gfp, indicating bioavailable toluene to rhizosphere bacteria. When toluene was not introduced, 16.5% of the A506 (pTolLHB) cells recovered from the roots expressed gfp, indicating that natural inducers of the PtbuA1 promoter were present in the barley rhizosphere. When introduced into rhizotrons containing barley plants and toluene vapours, the biosensor allowed localization of the availability of toluene along the seminal roots. In rhizotrons that were not exposed to toluene vapours, the biosensor exhibited high PtbuA1 -promoter activity in distinct regions along the seminal roots, indicating spatial heterogeneity plant- or rhizosphere microbial community-derived inducers of the PtbuA1 promoter. This recombination-based toluene biosensor thus was useful in identifying bacterial exposure to transient or low levels of toluene, or related compounds, directly in the environment. [source] Molecular ecology of global changeMOLECULAR ECOLOGY, Issue 19 2007THORSTEN B. H. REUSCH Abstract Global environmental change is altering the selection regime for all biota. The key selective factors are altered mean, variance and seasonality of climatic variables and increase in CO2 concentration itself. We review recent studies that document rapid evolution to global climate change at the phenotypic and genetic level, as a response to shifts in these factors. Among the traits that have changed are photoperiod responses, stress tolerance and traits associated with enhanced dispersal. The genetic basis of two traits with a critical role under climate change, stress tolerance and photoperiod behaviour, is beginning to be understood for model organisms, providing a starting point for candidate gene approaches in targeted nonmodel species. Most studies that have documented evolutionary change are correlative, while selection experiments that manipulate relevant variables are rare. The latter are particularly valuable for prediction because they provide insight into heritable change to simulated future conditions. An important gap is that experimental selection regimes have mostly been testing one variable at a time, while synergistic interactions are likely under global change. The expanding toolbox available to molecular ecologists holds great promise for identifying the genetic basis of many more traits relevant to fitness under global change. Such knowledge, in turn, will significantly advance predictions on global change effects because presence and polymorphism of critical genes can be directly assessed. Moreover, knowledge of the genetic architecture of trait correlations will provide the necessary framework for understanding limits to phenotypic evolution; in particular as lack of critical gene polymorphism or entire pathways, metabolic costs of tolerance and linkage or pleiotropy causing negative trait correlations. Synergism among stressor impacts on organismal function may be causally related to conflict among transcriptomic syndromes specific to stressor types. Because adaptation to changing environment is always contingent upon the spatial distribution of genetic variation, high-resolution estimates of gene flow and hybridization should be used to inform predictions of evolutionary rates. [source] The role of DNA methylation, nucleosome occupancy and histone modifications in paramutationTHE PLANT JOURNAL, Issue 3 2010Max Haring Summary Paramutation is the transfer of epigenetic information between alleles that leads to a heritable change in expression of one of these alleles. Paramutation at the tissue-specifically expressed maize (Zea mays) b1 locus involves the low-expressing B, and high-expressing B-I allele. Combined in the same nucleus, B, heritably changes B-I into B,. A hepta-repeat located 100-kb upstream of the b1 coding region is required for paramutation and for high b1 expression. The role of epigenetic modifications in paramutation is currently not well understood. In this study, we show that the B, hepta-repeat is DNA-hypermethylated in all tissues analyzed. Importantly, combining B, and B-I in one nucleus results in de novo methylation of the B-I repeats early in plant development. These findings indicate a role for hepta-repeat DNA methylation in the establishment and maintenance of the silenced B, state. In contrast, nucleosome occupancy, H3 acetylation, and H3K9 and H3K27 methylation are mainly involved in tissue-specific regulation of the hepta-repeat. Nucleosome depletion and H3 acetylation are tissue-specifically regulated at the B-I hepta-repeat and associated with enhancement of b1 expression. H3K9 and H3K27 methylation are tissue-specifically localized at the B, hepta-repeat and reinforce the silenced B, chromatin state. The B, coding region is H3K27 dimethylated in all tissues analyzed, indicating a role in the maintenance of the silenced B, state. Taken together, these findings provide insight into the mechanisms underlying paramutation and tissue-specific regulation of b1 at the level of chromatin structure. [source] Assessing human germ-cell mutagenesis in the Postgenome Era: A celebration of the legacy of William Lawson (Bill) Russell,ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2 2007Andrew J. Wyrobek Abstract Birth defects, de novo genetic diseases, and chromosomal abnormality syndromes occur in ,5% of all live births, and affected children suffer from a broad range of lifelong health consequences. Despite the social and medical impact of these defects, and the 8 decades of research in animal systems that have identified numerous germ-cell mutagens, no human germ-cell mutagen has been confirmed to date. There is now a growing consensus that the inability to detect human germ-cell mutagens is due to technological limitations in the detection of random mutations rather than biological differences between animal and human susceptibility. A multidisciplinary workshop responding to this challenge convened at The Jackson Laboratory in Bar Harbor, Maine. The purpose of the workshop was to assess the applicability of an emerging repertoire of genomic technologies to studies of human germ-cell mutagenesis. Workshop participants recommended large-scale human germ-cell mutation studies be conducted using samples from donors with high-dose exposures, such as cancer survivors. Within this high-risk cohort, parents and children could be evaluated for heritable changes in (a) DNA sequence and chromosomal structure, (b) repeat sequences and minisatellites, and (c) global gene expression profiles and pathways. Participants also advocated the establishment of a bio-bank of human tissue samples from donors with well-characterized exposure, including medical and reproductive histories. This mutational resource could support large-scale, multiple-endpoint studies. Additional studies could involve the examination of transgenerational effects associated with changes in imprinting and methylation patterns, nucleotide repeats, and mitochondrial DNA mutations. The further development of animal models and the integration of these with human studies are necessary to provide molecular insights into the mechanisms of germ-cell mutations and to identify prevention strategies. Furthermore, scientific specialty groups should be convened to review and prioritize the evidence for germ-cell mutagenicity from common environmental, occupational, medical, and lifestyle exposures. Workshop attendees agreed on the need for a full-scale assault to address key fundamental questions in human germ-cell environmental mutagenesis. These include, but are not limited to, the following: Do human germ-cell mutagens exist? What are the risks to future generations? Are some parents at higher risk than others for acquiring and transmitting germ-cell mutations? Obtaining answers to these, and other critical questions, will require strong support from relevant funding agencies, in addition to the engagement of scientists outside the fields of genomics and germ-cell mutagenesis. Environ. Mol. Mutagen., 2007. Published 2007 Wiley-Liss, Inc. [source] Linking movement behaviour, dispersal and population processes: is individual variation a key?JOURNAL OF ANIMAL ECOLOGY, Issue 5 2009Colin Hawkes Summary 1Movement behaviour has become increasingly important in dispersal ecology and dispersal is central to the development of spatially explicit population ecology. The ways in which the elements have been brought together are reviewed with particular emphasis on dispersal distance distributions and the value of mechanistic models. 2There is a continuous range of movement behaviours and in some species, dispersal is a clearly delineated event but not in others. The biological complexities restrict conclusions to high-level generalizations but there may be principles that are common to dispersal and other movements. 3Random walk and diffusion models when appropriately elaborated can provide an understanding of dispersal distance relationships on spatial and temporal scales relevant to dispersal. Leptokurtosis in the relationships may be the result of a combination of factors including population heterogeneity, correlation, landscape features, time integration and density dependence. The inclusion in diffusion models of individual variation appears to be a useful elaboration. The limitations of the negative exponential and other phenomenological models are discussed. 4The dynamics of metapopulation models are sensitive to what appears to be small differences in the assumptions about dispersal. In order to represent dispersal realistically in population models, it is suggested that phenomenological models should be replaced by those based on movement behaviour incorporating individual variation. 5The conclusions are presented as a set of candidate principles for evaluation. The main features of the principles are that uncorrelated or correlated random walk, not linear movement, is expected where the directions of habitat patches are unpredictable and more complex behaviour when organisms have the ability to orientate or navigate. Individuals within populations vary in their movement behaviour and dispersal; part of this variation is a product of random elements in movement behaviour and some of it is heritable. Local and metapopulation dynamics are influenced by population heterogeneity in dispersal characteristics and heritable changes in dispersal propensity occur on time-scales short enough to impact population dynamics. [source] X-linked mental retardation and epigeneticsJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 4 2006Guy Froyen Abstract The search for the genetic defects in constitutional diseases has so far been restricted to direct methods for the identification of genetic mutations in the patients' genome. Traditional methods such as karyotyping, FISH, mutation screening, positional cloning and CGH, have been complemented with newer methods including array-CGH and PCR-based approaches (MLPA, qPCR). These methods have revealed a high number of genetic or genomic aberrations that result in an altered expression or reduced functional activity of key proteins. For a significant percentage of patients with congenital disease however, the underlying cause has not been resolved strongly suggesting that yet other mechanisms could play important roles in their etiology. Alterations of the ,native' epigenetic imprint might constitute such a novel mechanism. Epigenetics, heritable changes that do not rely on the nucleotide sequence, has already been shown to play a determining role in embryonic development, X-inactivation, and cell differentiation in mammals. Recent progress in the development of techniques to study these processes on full genome scale has stimulated researchers to investigate the role of epigenetic modifications in cancer as well as in constitutional diseases. We will focus on mental impairment because of the growing evidence for the contribution of epigenetics in memory formation and cognition. Disturbance of the epigenetic profile due to direct alterations at genomic regions, or failure of the epigenetic machinery due to genetic mutations in one of its components, has been demonstrated in cognitive derangements in a number of neurological disorders now. It is therefore tempting to speculate that the cognitive deficit in a significant percentage of patients with unexplained mental retardation results from epigenetic modifications. [source] DNA methylation: an epigenetic pathway to cancer and a promising target for anticancer therapyJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 8 2002Jesper Worm Abstract The unique properties of a cancer cell are acquired through a stepwise accumulation of heritable changes in the information content of proto-oncogenes and tumor suppressor genes. While gain, loss, and mutation of genetic information have long been known to contribute to tumorigenesis, it has been increasingly recognized over the past 5 years that ,epigenetic' mechanisms may play an equally important role. The main epigenetic modification of the human genome is methylation of cytosine residues within the context of the CpG dinucleotide. De novo methylation of ,CpG islands' in the promoter regions of tumor suppressor genes may lead to transcriptional silencing through a complex process involving histone deacetylation and chromatin condensation, and thus represents a tumorigenic event that is functionally equivalent to genetic changes like mutation and deletion. DNA methylation is interesting from a diagnostic viewpoint because it may be easily detected in DNA released from neoplastic and preneoplastic lesions into serum, urine or sputum, and from a therapeutic viewpoint because epigenetically silenced genes may be reactivated by inhibitors of DNA methylation and/or histone deacetylase. A better understanding of epigenetic mechanisms leading to tumor formation and chemoresistance may eventually improve current cancer treatment regimens and be instructive for a more rational use of anticancer agents. [source] Epigenetic changes in cancer,APMIS, Issue 10 2007KIRSTEN GRØNBÆK A cancer develops when a cell acquires specific growth advantages through the stepwise accumulation of heritable changes in gene function. Basically, this process is directed by changes in two different classes of genes: Tumor suppressor genes that inhibit cell growth and survival and oncogenes that promote cell growth and survival. Since several alterations are usually required for a cancer to fully develop, the malignant phenotype is determined by the compound status of tumor suppressor genes and oncogenes. Cancer genes may be changed by several mechanisms, which potentially alter the protein encoding nucleotide template, change the copy number of genes, or lead to increased gene transcription. Epigenetic alterations, which, by definition, comprise mitotically and meiotically heritable changes in gene expression that are not caused by changes in the primary DNA sequence, are increasingly being recognized for their roles in carcinogenesis. These epigenetic alterations may involve covalent modifications of amino acid residues in the histones around which the DNA is wrapped, and changes in the methylation status of cytosine bases (C) in the context of CpG dinucleotides within the DNA itself. Methylation of clusters of CpGs called "CpG-islands" in the promoters of genes has been associated with heritable gene silencing. The present review will focus on how disruption of the epigenome can contribute to cancer. In contrast to genetic alterations, gene silencing by epigenetic modifications is potentially reversible. Treatment by agents that inhibit cytosine methylation and histone deacetylation can initiate chromatin decondensation, demethylation and reestablishment of gene transcription. Accordingly, in the clinical setting, DNA methylation and histone modifications are very attractive targets for the development and implementation of new therapeutic approaches. Many clinical trials are ongoing, and epigenetic therapy has recently been approved by the United States Food and Drug Administration (US FDA) for use in the treatment of myelodysplastic syndrome (MDS) and primary cutaneous T-cell lymphoma (CTCL). [source] A new perspective on Darwin's PangenesisBIOLOGICAL REVIEWS, Issue 2 2008Yongsheng Liu Abstract In 1868 Charles Darwin proposed Pangenesis, a developmental theory of heredity. He suggested that all cells in an organism are capable of shedding minute particles he called gemmules, which are able to circulate throughout the body and finally congregate in the gonads. These particles are then transmitted to the next generation and are responsible for the transmission of characteristics from parent to offspring. If any cells of the parent undergo changes as a result of environmental change, they will consequently transmit modified gemmules to their offspring. Soon after Darwin's pangenetic theory was published, Francis Galton designed a series of blood transfusion experiments on differently pigmented rabbits to test its validity. He found no evidence in support of the existence of Darwin's gemmules and the concept of Pangenesis was largely abandoned. In this article, recent reports of successful induction of heritable changes by blood transfusion are reviewed. Detection of circulating nucleic acids and prions in plant sap and animal blood is considered as fresh evidence for the existence of gemmules. It is now apparent that a considerable revision of views on Darwin's Pangenesis must occur before a new comprehensive genetic theory can be achieved. [source] The Emerging Therapeutic Potential of Histone Methyltransferase and Demethylase InhibitorsCHEMMEDCHEM, Issue 10 2009Astrid Spannhoff Dr. Abstract Epigenetics is defined as heritable changes to the transcriptome that are independent of changes in the genome. The biochemical modifications that govern epigenetics are DNA methylation and posttranslational histone modifications. Among the histone modifications, acetylation and deacetylation are well characterized, whereas the fields of histone methylation and especially demethylation are still in their infancy. This is particularly true with regard to drug discovery. There is strong evidence that these modifications play an important role in the maintenance of transcription as well as in the development of certain diseases. This article gives an overview of the mechanisms of action of histone methyltransferases and demethylases, their role in the formation of certain diseases, and available inhibitors. Special emphasis is placed on the strategies that led to the first inhibitors which are currently available and the screening approaches that were used in that process. [source] | |||||||||||||