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31.
Bjorn T. Adalsteinsson Haukur Gudnason Thor Aspelund Tamara B. Harris Lenore J. Launer Gudny Eiriksdottir Albert V. Smith Vilmundur Gudnason 《PloS one》2012,7(10)
Epigenetic studies are commonly conducted on DNA from tissue samples. However, tissues are ensembles of cells that may each have their own epigenetic profile, and therefore inter-individual cellular heterogeneity may compromise these studies. Here, we explore the potential for such confounding on DNA methylation measurement outcomes when using DNA from whole blood. DNA methylation was measured using pyrosequencing-based methodology in whole blood (n = 50–179) and in two white blood cell fractions (n = 20), isolated using density gradient centrifugation, in four CGIs (CpG Islands) located in genes HHEX (10 CpG sites assayed), KCNJ11 (8 CpGs), KCNQ1 (4 CpGs) and PM20D1 (7 CpGs). Cellular heterogeneity (variation in proportional white blood cell counts of neutrophils, lymphocytes, monocytes, eosinophils and basophils, counted by an automated cell counter) explained up to 40% (p<0.0001) of the inter-individual variation in whole blood DNA methylation levels in the HHEX CGI, but not a significant proportion of the variation in the other three CGIs tested. DNA methylation levels in the two cell fractions, polymorphonuclear and mononuclear cells, differed significantly in the HHEX CGI; specifically the average absolute difference ranged between 3.4–15.7 percentage points per CpG site. In the other three CGIs tested, methylation levels in the two fractions did not differ significantly, and/or the difference was more moderate. In the examined CGIs, methylation levels were highly correlated between cell fractions. In summary, our analysis detects region-specific differential DNA methylation between white blood cell subtypes, which can confound the outcome of whole blood DNA methylation measurements. Finally, by demonstrating the high correlation between methylation levels in cell fractions, our results suggest a possibility to use a proportional number of a single white blood cell type to correct for this confounding effect in analyses. 相似文献
32.
Southwell J Chowdhury SF Gottlieb B Beitel LK Lumbroso R Purisima EO Trifiro M 《The Journal of steroid biochemistry and molecular biology》2008,111(1-2):138-146
Prostate cancer may progress by circumventing ablation therapy due to mutations in the androgen receptor (AR) gene. The most intensively studied is the T877A mutation in the ligand binding domain (LBD), which causes the AR to become promiscuous, i.e., respond to a number of different ligands. Our investigations have shown that the T877A mutation alters the inverse relationship between CAG repeat length and transactivation in a noticeable albeit minor manner, while increasing N/C terminal interactions. In the presence of beta-catenin, a coactivator over-expressed in prostate cancer, the inverse relationship between CAG repeat length and transactivation is reversed for the wild type (wt) AR as well. We have also used molecular modeling with the AR and FXXLF and LXXLL peptides to investigate N/C terminal and coactivator interactions. In T877A, this approach revealed an increase in the flexibility of amino acid residues in the activation function 2 (AF-2) domain in the LBD, and a larger solvent accessible surface in T877A compared to the wt AR AF-2 domain. Thus, the improved induced fit of the AR N-terminal domain FXXLF-containing peptide into the T877A LBD could be due to the increased flexibility and solvent accessibility of the AF-2 domain. These new observations suggest that the AR CAG effect can be overridden by prostate cancer mutations, and also further our understanding of hormone-refractory prostate cancer by helping to explain the promiscuity of the T877A mutation. 相似文献
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Matthew Menke Jonathan King Bonnie Berger Lenore Cowen 《Journal of computational biology》2005,12(6):777-795
A method is presented that uses beta-strand interactions at both the sequence and the atomic level, to predict beta-structural motifs of protein sequences. A program called Wrap-and- Pack implements this method and is shown to recognize beta-trefoils, an important class of globular beta-structures, in the Protein Data Bank with 92% specificity and 92.3% sensitivity in cross-validation. It is demonstrated that Wrap-and-Pack learns each of the ten known SCOP beta-trefoil families, when trained primarily on beta-structures that are not beta-trefoils, together with three-dimensional structures of known beta-trefoils from outside the family. Wrap-and-Pack also predicts many proteins of unknown structure to be beta-trefoils. The computational method used here may generalize to other beta-structures for which strand topology and profiles of residue accessibility are well conserved. 相似文献
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We used abundance data and the program Focus to determine the spatial scale at which 31 species of longhorned beetles (Coleoptera: Cerambycidae) respond to forest habitat amount. We predicted that the spatial scale at which species respond would increase with body size, and that species using ephemeral larval habitat would respond at larger spatial scales than species using more stable larval habitat. We found that forest cover was a better measure of the amount of habitat for polyphagous species than for oligophagous species. Larger species of longhorned beetles responded to forest cover at larger scales. We did not find evidence that species using more ephemeral larval habitat conditions responded at larger scales than species developing in more stable habitat conditions. Our results highlight the importance of accurately describing habitat in studies of species–environment relationships. While scales of response may be species-specific, some generalizations across species are possible. 相似文献