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  • 1
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    Fingerprinting protein structures effectively and efficiently (2014)
    Oxford University Press
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    Publication Date: 2014-03-28
    Description: Motivation:  One common task in structural biology is to assess the similarities and differences among protein structures. A variety of structure alignment algorithms and programs has been designed and implemented for this purpose. A major drawback with existing structure alignment programs is that they require a large amount of computational time, rendering them infeasible for pairwise alignments on large collections of structures. To overcome this drawback, a fragment alphabet learned from known structures has been introduced. The method, however, considers local similarity only, and therefore occasionally assigns high scores to structures that are similar only in local fragments. Method:  We propose a novel approach that eliminates false positives, through the comparison of both local and remote similarity, with little compromise in speed. Two kinds of contact libraries (ContactLib) are introduced to fingerprint protein structures effectively and efficiently. Each contact group of the contact library consists of one local or two remote fragments and is represented by a concise vector. These vectors are then indexed and used to calculate a new combined hit-rate score to identify similar protein structures effectively and efficiently. Results:  We tested our method on the high-quality protein structure subset of SCOP30 containing 3297 protein structures. For each protein structure of the subset, we retrieved its neighbor protein structures from the rest of the subset. The best area under the Receiver-Operating Characteristic curve, archived by ContactLib, is as high as 0.960. This is a significant improvement compared with 0.747, the best result achieved by FragBag. We also demonstrated that incorporating remote contact information is critical to consistently retrieve accurate neighbor protein structures for all- query protein structures. Availability and implementation:   https://cs.uwaterloo.ca/~xfcui/contactlib/ . Contact:   shuaicli@cityu.edu.hk or mli@uwaterloo.ca
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 2
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    Matrix completion via an alternating direction method (2012)
    Oxford University Press
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    Publication Date: 2012-01-20
    Description: The matrix completion problem is to complete an unknown matrix from a small number of entries, and it captures many applications in diversified areas. Recently, it was shown that completing a low-rank matrix can be successfully accomplished by solving its convex relaxation problem using the nuclear norm. This paper shows that the alternating direction method (ADM) is applicable for completing a low-rank matrix including the noiseless case, the noisy case and the positive semidefinite case. The ADM approach for the matrix completion problem is easily implementable and very efficient. Numerical comparisons of the ADM approach with some state-of-the-art methods are reported.
    Print ISSN: 0272-4979
    Electronic ISSN: 1464-3642
    Topics: Mathematics
    Published by Oxford University Press
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  • 3
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    Direct activation of human and mouse Oct4 genes using engineered TALE and Cas9 transcription factors (2014)
    Oxford University Press
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    Publication Date: 2014-04-15
    Description: The newly developed transcription activator-like effector protein (TALE) and clustered regularly interspaced short palindromic repeats/Cas9 transcription factors (TF) offered a powerful and precise approach for modulating gene expression. In this article, we systematically investigated the potential of these new tools in activating the stringently silenced pluripotency gene Oct4 ( Pou5f1 ) in mouse and human somatic cells. First, with a number of TALEs and sgRNAs targeting various regions in the mouse and human Oct4 promoters, we found that the most efficient TALE-VP64s bound around –120 to –80 bp, while highly effective sgRNAs targeted from –147 to –89-bp upstream of the transcription start sites to induce high activity of luciferase reporters. In addition, we observed significant transcriptional synergy when multiple TFs were applied simultaneously. Although individual TFs exhibited marginal activity to up-regulate endogenous gene expression, optimized combinations of TALE-VP64s could enhance endogenous Oct4 transcription up to 30-fold in mouse NIH3T3 cells and 20-fold in human HEK293T cells. More importantly, the enhancement of OCT4 transcription ultimately generated OCT4 proteins. Furthermore, examination of different epigenetic modifiers showed that histone acetyltransferase p300 could enhance both TALE-VP64 and sgRNA/dCas9-VP64 induced transcription of endogenous OCT4 . Taken together, our study suggested that engineered TALE-TF and dCas9-TF are useful tools for modulating gene expression in mammalian cells.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 4
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    Young intragenic miRNAs are less coexpressed with host genes than old ones: implications of miRNA-host gene coevolution (2012)
    Oxford University Press
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    Publication Date: 2012-05-13
    Description: MicroRNAs (miRNAs) have emerged as key regulators of gene expression. Intragenic miRNAs account for ~50% of mammalian miRNAs. Classic studies reported that they are usually coexpressed with host genes. Here, using genome-wide miRNA and gene expression profiles from five sample sets, we show that evolutionarily conserved (‘old’) intragenic miRNAs tend to be coexpressed with host genes, but non-conserved (‘young’) ones rarely do so. This result is robust: in all sample sets, the coexpression rate of young miRNAs is significantly lower than that of conserved ones even after controlling for abundance. As a result, although young miRNAs dominate in human genome, the majority of intragenic miRNAs that show coexpression with host genes are phylogenetically old ones. For younger miRNAs, extrapolation of their expression profiles from those of their host genes should be treated with caution. We propose a model to explain this phenomenon in which the majority of young miRNAs are unlikely to be coexpressed with host genes; however, for some fraction of young miRNAs coexpression with their host genes, initially imbued by chromatin level effects, is advantageous and these are the ones likely to embed into the system and evolve ever higher levels of coexpression, possibly by evolving piggybacking mechanisms.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    Genome-Wide Analyses of a Plant-Specific LIM-Domain Gene Family Implicate Its Evolutionary Role in Plant Diversification (2014)
    Oxford University Press
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    Publication Date: 2014-05-01
    Description: The Arabidopsis DA1 genes appear to have multiple functions in regulating organ size and abiotic stress response, but the biological roles of its closely related genes remain unknown. Evolutionary analyses might provide some clues to aid in an understanding of their functional diversification. In this work, we characterized the molecular evolution and expressional diversification of DA1 -like genes. Surveying 354 sequenced genomes revealed 142 DA1 -like genes only in plants, indicating plant-specificity of these genes. The DA1-like protein modular structure was composed of two UIMs (ubiquitin interaction motifs), one LIM-domain (from lin-11 , isl-1 , and mec-3 ), and a conserved C-terminal, and was distinguishable from the already defined three groups of LIM-domain proteins. We further found that the DA1 -like genes diverged into Classes I and II at the ancestor of seed plants and acquired 13 clade-specific residues during their evolutionary history. Moreover, diverse intron size evolution was noted following the transition from size-expandable introns to minimal ones, accompanying the emergence and diversification of angiosperms. Functional diversification as it relates to gene expression was further investigated in soybean. Glycine max DA1 genes showed diverse tissues expression patterns during development and had substantially varied abiotic stress response expression. Thus, variations in the coding regions, intron size, and gene expression contributed to the functional diversification of this gene family. Our data suggest that the evolution of the DA1 -like genes facilitated the development of diverse molecular and functional diversification patterns to accompany the successful radiation of plants into diverse environments during evolution.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    Molecular mechanisms of two-component system RhpRS regulating type III secretion system in Pseudomonas syringae (2014)
    Oxford University Press
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    Publication Date: 2014-10-10
    Description: Pseudomonas syringae uses the two-component system RhpRS to regulate the expression of type III secretion system (T3SS) genes and bacterial virulence. However, the molecular mechanisms and the regulons of RhpRS have yet to be fully elucidated. Here, we show that RhpS functions as a kinase and a phosphatase on RhpR and as an autokinase upon itself. RhpR is phosphorylated by the small phosphodonor acetyl phosphate. A specific RhpR-binding site containing the inverted repeat (IR) motif GTATC-N 6 -GATAC, was mapped to its own promoter by a DNase I footprint analysis. Electrophoretic mobility shift assay indicated that P-RhpR has a higher binding affinity to the IR motif than RhpR. To identify additional RhpR targets in P. syringae , we performed chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-seq) and detected 167 enriched loci including the hrpR promoter, suggesting the direct regulation of T3SS cascade genes by RhpR. A genome-wide microarray analysis showed that, in addition to the T3SS cascade genes, RhpR differentially regulates a large set of genes with various functions in response to different growth conditions. Together, these results suggested that RhpRS is a global regulator that allows P. syringae to sense and respond to environmental changes by coordinating T3SS expression and many other biological processes.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    Nucleosome eviction and multiple co-factor binding predict estrogen-receptor-alpha-associated long-range interactions (2014)
    Oxford University Press
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    Publication Date: 2014-06-21
    Description: Many enhancers regulate their target genes via long-distance interactions. High-throughput experiments like ChIA-PET have been developed to map such largely cell-type-specific interactions between cis -regulatory elements genome-widely. In this study, we integrated multiple types of data in order to reveal the general hidden patterns embedded in the ChIA-PET data. We found characteristic distance features related to promoter–promoter, enhancer–enhancer and insulator–insulator interactions. Although a protein may have many binding sites along the genome, our hypothesis is that those sites that share certain open chromatin structure can accommodate relatively larger protein complex consisting of specific regulatory and ‘bridging’ factors, and may be more likely to form robust long-range deoxyribonucleic acid (DNA) loops. This hypothesis was validated in the estrogen receptor alpha (ERα) ChIA-PET data. An efficient classifier was built to predict ERα-associated long-range interactions solely from the related ChIP-seq data, hence linking distal ERα-dependent enhancers to their target genes. We further applied the classifier to generate additional novel interactions, which were undetected in the original ChIA-PET paper but were validated by other independent experiments. Our work provides a new insight into the long-range chromatin interactions through deeper and integrative ChIA-PET data analysis and demonstrates DNA looping predictability from ordinary ChIP-seq data.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 8
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    Genome-wide DNA hydroxymethylation changes are associated with neurodevelopmental genes in the developing human cerebellum (2012)
    Oxford University Press
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    Publication Date: 2012-12-07
    Description: 5-Hydroxymethylcytosine (5-hmC) is a newly discovered modified form of cytosine that has been suspected to be an important epigenetic modification in neurodevelopment. While DNA methylation dynamics have already been implicated during neurodevelopment, little is known about hydroxymethylation in this process. Here, we report DNA hydroxymethylation dynamics during cerebellum development in the human brain. Overall, we find a positive correlation between 5-hmC levels and cerebellum development. Genome-wide profiling reveals that 5-hmC is highly enriched on specific gene regions including exons and especially the untranslated regions (UTRs), but it is depleted on introns and intergenic regions. Furthermore, we have identified fetus-specific and adult-specific differentially hydroxymethylated regions (DhMRs), most of which overlap with genes and CpG island shores. Surprisingly, during development, DhMRs are highly enriched in genes encoding mRNAs that can be regulated by fragile X mental retardation protein (FMRP), some of which are disrupted in autism, as well as in many known autism genes. Our results suggest that 5-hmC-mediated epigenetic regulation may broadly impact the development of the human brain, and its dysregulation could contribute to the molecular pathogenesis of neurodevelopmental disorders. Accession number: Sequencing data have been deposited to GEO with accession number GSE40539.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 9
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    A genome-wide association study of early menopause and the combined impact of identified variants (2013)
    Perry, J. R. B., Corre, T., Esko, T., Chasman, D. I., Fischer, K., Franceschini, N., He, C., Kutalik, Z., Mangino, M., Rose, L. M., Vernon Smith, A., Stolk, L., Sulem, P., Weedon, M. N., Zhuang, W. V., Arnold, A., Ashworth, A., Bergmann, S., Buring, J. E., Burri, A., Chen, C., Cornelis, M. C., Couper, D. J., Goodarzi, M. O., Gudnason, V., Harris, T., Hofman, A., Jones, M., Kraft, P., Launer, L., Laven, J. S. E., Li, G., McKnight, B., Masciullo, C., Milani, L., Orr, N., Psaty, B. M., Repro; Gen Consortium, Ridker, P. M., Rivadeneira, F., Sala, C., Salumets, A., Schoemaker, M., Traglia, M., Waeber, G., Chanock, S. J., Demerath, E. W., Garcia, M., Hankinson, S. E., Hu, F. B., Hunter, D. J., Lunetta, K. L., Metspalu, A., Montgomery, G. W., Murabito, J. M., Newman, A. B., Ong, K. K., Spector, T. D., Stefansson, K., Swerdlow, A. J., Thorsteinsdottir, U., Van Dam, R. M., Uitterlinden, A. G., Visser, J. A., Vollenweider, P., Toniolo, D., Murray, A.
    Oxford University Press
    Details
    Publication Date: 2013-03-15
    Description: Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ~30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 10
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    A meta-analysis of genome-wide association studies for adiponectin levels in East Asians identifies a novel locus near WDR11-FGFR2 (2014)
    Oxford University Press
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    Publication Date: 2014-01-24
    Description: Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 ( P = 3.0 x 10 –14 ) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA ( P = 1.2 x 10 –7 ). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 ( P = 6.8 x 10 –165 ), ADIPOQ ( P = 1.8 x 10 –22 ), PEPD ( P = 3.6 x 10 –12 ), CMIP ( P = 2.1 x 10 –10 ), ZNF664 ( P = 2.3 x 10 –7 ) and GPR109A ( P = 7.4 x 10 –6 ). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP ( P initial = 0.020; P conditional = 7.0 x 10 –7 ). We further confirmed the independence of two pairs of closely located loci (〈2 Mb) on chromosome 16 at CMIP and CDH13 , and on chromosome 12 at GPR109A and ZNF664 . In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides ( P = 3.3 x 10 –4 ), high density lipoprotein cholesterol (HDL-C, P = 4.9 x 10 –4 ) and body mass index (BMI)-adjusted waist–hip ratio ( P = 9.8 x 10 –3 ). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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