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  • 1
    Language: English
    In: PLoS Genetics, 2009, Vol.5(6), p.e1000509
    Description: Asymmetric strand segregation has been proposed as a mechanism to minimize effective mutation rates in epithelial tissues. Under asymmetric strand segregation, the double-stranded molecule that contains the oldest DNA strand is preferentially targeted to the somatic stem cell after each round of DNA replication. This oldest DNA strand is expected to have fewer errors than younger strands because some of the errors that arise on daughter strands during their synthesis fail to be repaired. Empirical findings suggest the possibility of asymmetric strand segregation in a subset of mammalian cell lineages, indicating that it may indeed function to increase genetic fidelity. However, the implications of asymmetric strand segregation for the fidelity of epigenetic information remain unexplored. Here, I explore the impact of strand-segregation dynamics on epigenetic fidelity using a mathematical-modelling approach that draws on the known molecular mechanisms of DNA methylation and existing rate estimates from empirical methylation data. I find that, for a wide range of starting methylation densities, asymmetric—but not symmetric—strand segregation leads to systematic increases in methylation levels if parent strands are subject to de novo methylation events. I found that epigenetic fidelity can be compromised when enhanced genetic fidelity is achieved through asymmetric strand segregation. Strand segregation dynamics could thus explain the increased DNA methylation densities that are observed in structured cellular populations during aging and in disease. ; Through my investigations of the fidelity of epigenetic inheritance, I became intrigued by the interplay of genetic and epigenetic fidelities. Cairns proposed in 1975 that the lifetime risk of epithelial cancers would be reduced if chromosomes containing the oldest DNA strands were selectively segregated to somatic stem cells. I wondered about the implications of such asymmetric strand segregation for the fidelity of epigenetic information. To address this issue, I modelled the partitioning of DNA molecules after replication, with special attention to the molecule that contained the oldest strand. I found that the enhanced genetic fidelity that may be achieved through asymmetric strand segregation could, under some scenarios, compromise epigenetic fidelity. I am excited to pursue these studies as they apply to epigenetic changes observed to occur during aging and in human diseases, including several cancers.
    Keywords: Research Article ; Cell Biology -- Developmental Molecular Mechanisms ; Developmental Biology -- Aging ; Evolutionary Biology ; Genetics And Genomics -- Cancer Genetics ; Genetics And Genomics -- Epigenetics
    ISSN: 1553-7390
    E-ISSN: 1553-7404
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  • 2
    Language: English
    In: PLoS ONE, 2012, Vol.7(3), p.e32225
    Description: DNA methyltransferases establish methylation patterns in cells and transmit these patterns over cell generations, thereby influencing each cell's epigenetic states. Three primary DNA methyltransferases have been identified in mammals: DNMT1, DNMT3A and DNMT3B. Extensive in vitro studies have investigated key properties of these enzymes, namely their substrate specificity and processivity. Here we study these properties in vivo, by applying novel statistical analysis methods to double-stranded DNA methylation patterns collected using hairpin-bisulfite PCR. Our analysis fits a novel Hidden Markov Model (HMM) to the observed data, allowing for potential bisulfite conversion errors, and yields statistical estimates of parameters that quantify enzyme processivity and substrate specificity. We apply this model to methylation patterns established in vivo at three loci in humans: two densely methylated inactive X (Xi)-linked loci ( and ), and an autosomal locus ( ), where methylation densities are tissue-specific but moderate. We find strong evidence for a high level of processivity of DNMT1 at and , with the mean association tract length being a few hundred base pairs. Regardless of tissue types, methylation patterns at are dominated by DNMT1 maintenance events, similar to the two Xi-linked loci, but are insufficiently informative regarding processivity to draw any conclusions about processivity at that locus. At all three loci we find that DNMT1 shows a strong preference for adding methyl groups to hemi-methylated CpG sites over unmethylated sites. The data at all three loci also suggest low (possibly 0) association of the de novo methyltransferases, the DNMT3s, and are consequently uninformative about processivity or preference of these enzymes. We also extend our HMM to reanalyze published data on mouse DNMT1 activities in vitro. The results suggest shorter association tracts (and hence weaker processivity), and much longer non-association tracts than human DNMT1 in vivo.
    Keywords: Research Article ; Biology ; Mathematics ; Physics ; Genetics And Genomics ; Molecular Biology ; Computational Biology ; Biophysics ; Physics ; Biochemistry ; Mathematics
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: Human Genetics, 2013, Vol.132(6), pp.715-717
    ISSN: 0340-6717
    E-ISSN: 1432-1203
    Source: Springer Science & Business Media B.V.
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  • 4
    Language: English
    In: PLoS ONE, 01 January 2011, Vol.6(8), p.e23648
    Description: Variability among individuals in the severity of fragile X syndrome (FXS) is influenced by epigenetic methylation mosaicism, which may also be common in other complex disorders. The epigenetic signal of dense promoter DNA methylation is usually associated with gene silencing, as was initially...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 19 April 2005, Vol.102(16), pp.5802-7
    Description: Cytosine methylation is an epigenetic mechanism in eukaryotes that is often associated with stable transcriptional silencing, such as in X-chromosome inactivation and genomic imprinting. Aberrant methylation patterns occur in several inherited human diseases and in many cancers. To understand how methylated and unmethylated states of cytosine residues are transmitted during DNA replication, we develop a population-epigenetic model of DNA methylation dynamics. The model is informed by our observation that de novo methylation can occur on the daughter strand while leaving the opposing cytosine unmethylated, as revealed by the patterns of methylation on the two complementary strands of individual DNA molecules. Under our model, we can infer site-specific rates of both maintenance and de novo methylation, values that determine the fidelity of methylation inheritance, from double-stranded methylation data. This approach can be used for populations of cells obtained from individuals without the need for cell culture. We use our method to infer cytosine methylation rates at several sites within the promoter of the human gene FMR1.
    Keywords: DNA Methylation ; Epigenesis, Genetic ; Models, Genetic ; DNA -- Metabolism
    ISSN: 0027-8424
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  • 6
    Language: English
    In: Genes & genetic systems, 2013-06, Vol.88(3), pp.211-224
    Description: Material Type: 記事・論文
    Keywords: Fragile X (Fmr1) Mutation Rates ; Population Epigenetics ; Fragile X-Associated Tremor Ataxia Syndrome (Fxtas) ; Fragile X Primary Ovarian Insufficiency (Fxpoi) ; Advanced Maternal Age
    ISSN: 13417568
    E-ISSN: 18805779
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  • 7
    Language: English
    In: Human genetics, June 2013, Vol.132(6), pp.715-7
    Keywords: Fragile X Mental Retardation Protein -- Genetics
    ISSN: 03406717
    E-ISSN: 1432-1203
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  • 8
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(7), p.e68191
    Description: The survival of a species depends on its capacity to adjust to changing environmental conditions, and new stressors. Such new, anthropogenic stressors include the neonicotinoid class of crop-protecting agents, which have been implicated in the population declines of pollinating insects, including...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 9
    Language: English
    In: The Journal of Sustainable Real Estate, 2012, Vol.4(1), pp.198-211
    Description: Abstract A challenge for sustainable development on restored landscapes is to secure funding in perpetuity for restoration. We report on a project that has provided a stable source of long-term funding for restoration in conjunction with development of housing, a golf course, and other amenities. At the restored site, historic grazing and a dam system had degraded hydrology and vegetation. Post-restoration ecological metrics now indicate a five-fold increase in spawning trout, and doubling of bird species. Private funding supports prairie and wetlands restoration efforts through a contractual sales-transfer fee and homeowners’ dues. A naturalist coordinates restoration and land stewardship. The project provides a model for restorative-development projects supported in perpetuity.
    ISSN: 19498276
    E-ISSN: 19498284
    Source: JSTOR Sustainability
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  • 10
    Language: English
    In: Infection and immunity, February 2018, Vol.86(2)
    Description: To better understand the innate immune response to infection, we tracked gene expression in the duodenal mucosa of 11 Bangladeshi adults with cholera, using biopsy specimens obtained immediately after rehydration and 30 and 180 days later. We identified differentially expressed genes and performed an analysis to predict differentially regulated pathways and upstream regulators. During acute cholera, there was a broad increase in the expression of genes associated with innate immunity, including activation of the NF-κB, mitogen-activated protein kinase (MAPK), and Toll-like receptor (TLR)-mediated signaling pathways, which, unexpectedly, persisted even 30 days after infection. Focusing on early differences in gene expression, we identified 37 genes that were differentially expressed on days 2 and 30 across the 11 participants. These genes included the endosomal Toll-like receptor gene , which was expressed in lamina propria cells. Underscoring a potential role for endosomal TLR-mediated signaling , our pathway analysis found that interferon regulatory factor 7 and beta 1 and alpha 2 interferons were among the top upstream regulators activated during cholera. Among the innate immune effectors, we found that the gene for DUOX2, an NADPH oxidase involved in the maintenance of intestinal homeostasis, was upregulated in intestinal epithelial cells during cholera. Notably, the observed increases in and expression were also modeled when Caco-2 or THP-1 cells, respectively, were stimulated with live but not with heat-killed organisms or cholera toxin alone. These previously unidentified features of the innate immune response to extend our understanding of the mucosal immune signaling pathways and effectors activated following cholera.
    Keywords: Vibrio Cholerae ; Immune Mechanisms ; Mucosal Immunity ; Immunity, Innate ; Immunity, Mucosal ; Signal Transduction ; Cholera -- Immunology ; Vibrio Cholerae -- Immunology
    ISSN: 00199567
    E-ISSN: 1098-5522
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