SPOP-containing complex regulates SETD2 stability and H3K36me3-coupled alternative splicing
Trimethylation of histone H3K36 is a chromatin mark associated with active gene expression, which has been implicated in coupling transcription with mRNA splicing and DNA damage response. SETD2 is a major H3K36 trimethyltransferase, which has been implicated as a tumor suppressor in mammals. Here, we report the regulation of SETD2 protein stability by the proteasome system, and the identification of SPOP, a key subunit of the CUL3 ubiquitin E3 ligase complex, as a SETD2-interacting protein. We demonstrate that SPOP is critically involved in SETD2 stability control and that the SPOP/CUL3 complex is responsible for SETD2 pol...
Source: Nucleic Acids Research - January 8, 2017 Category: Research Authors: Zhu, K., Lei, P.-J., Ju, L.-G., Wang, X., Huang, K., Yang, B., Shao, C., Zhu, Y., Wei, G., Fu, X.-D., Li, L., Wu, M. Tags: Gene regulation, Chromatin and Epigenetics Source Type: research
Co-regulation of paralog genes in the three-dimensional chromatin architecture
Paralog genes arise from gene duplication events during evolution, which often lead to similar proteins that cooperate in common pathways and in protein complexes. Consequently, paralogs show correlation in gene expression whereby the mechanisms of co-regulation remain unclear. In eukaryotes, genes are regulated in part by distal enhancer elements through looping interactions with gene promoters. These looping interactions can be measured by genome-wide chromatin conformation capture (Hi-C) experiments, which revealed self-interacting regions called topologically associating domains (TADs). We hypothesize that paralogs sha...
Source: Nucleic Acids Research - January 8, 2017 Category: Research Authors: Ibn-Salem, J., Muro, E. M., Andrade-Navarro, M. A. Tags: Gene regulation, Chromatin and Epigenetics Source Type: research
Enabling the democratization of the genomics revolution with a fully integrated web-based bioinformatics platform
Continued advancements in sequencing technologies have fueled the development of new sequencing applications and promise to flood current databases with raw data. A number of factors prevent the seamless and easy use of these data, including the breadth of project goals, the wide array of tools that individually perform fractions of any given analysis, the large number of associated software/hardware dependencies, and the detailed expertise required to perform these analyses. To address these issues, we have developed an intuitive web-based environment with a wide assortment of integrated and cutting-edge bioinformatics to...
Source: Nucleic Acids Research - January 8, 2017 Category: Research Authors: Li, P.-E., Lo, C.-C., Anderson, J. J., Davenport, K. W., Bishop-Lilly, K. A., Xu, Y., Ahmed, S., Feng, S., Mokashi, V. P., Chain, P. S. G. Tags: Computational Methods, Genomics Data Resources and Analyses Source Type: research
Alignment-free Formula oligonucleotide frequency dissimilarity measure improves prediction of hosts from metagenomically-derived viral sequences
Viruses and their host genomes often share similar oligonucleotide frequency (ONF) patterns, which can be used to predict the host of a given virus by finding the host with the greatest ONF similarity. We comprehensively compared 11 ONF metrics using several k-mer lengths for predicting host taxonomy from among ~32 000 prokaryotic genomes for 1427 virus isolate genomes whose true hosts are known. The background-subtracting measure $d_2^*$ at k = 6 gave the highest host prediction accuracy (33%, genus level) with reasonable computational times. Requiring a maximum dissimilarity score for making predictions (thresholding) an...
Source: Nucleic Acids Research - January 8, 2017 Category: Research Authors: Ahlgren, N. A., Ren, J., Lu, Y. Y., Fuhrman, J. A., Sun, F. Tags: Computational Biology Source Type: research
Assembly of supramolecular DNA complexes containing both G-quadruplexes and i-motifs by enhancing the G-repeat-bearing capacity of i-motifs
The single-step assembly of supramolecular complexes containing both i-motifs and G-quadruplexes (G4s) is demonstrated. This can be achieved because the formation of four-stranded i-motifs appears to be little affected by certain terminal residues: a five-cytosine tetrameric i-motif can bear ten-base flanking residues. However, things become complex when different lengths of guanine-repeats are added at the 3' or 5' ends of the cytosine-repeats. Here, a series of oligomers d(XGiXC5X) and d(XC5XGiX) (X = A, T or none; i < 5) are designed to study the impact of G-repeats on the formation of tetrameric i-motifs. Our data d...
Source: Nucleic Acids Research - January 8, 2017 Category: Research Authors: Cao, Y., Gao, S., Yan, Y., Bruist, M. F., Wang, B., Guo, X. Tags: Chemical Biology and Nucleic Acid Chemistry Source Type: research
Visualization of self-delivering hydrophobically modified siRNA cellular internalization
siRNAs are a new class of therapeutic modalities with promising clinical efficacy that requires modification or formulation for delivery to the tissue and cell of interest. Conjugation of siRNAs to lipophilic groups supports efficient cellular uptake by a mechanism that is not well characterized. Here we study the mechanism of internalization of asymmetric, chemically stabilized, cholesterol-modified siRNAs (sd-rxRNAs®) that efficiently enter cells and tissues without the need for formulation. We demonstrate that uptake is rapid with significant membrane association within minutes of exposure followed by the formation ...
Source: Nucleic Acids Research - January 8, 2017 Category: Research Authors: Ly, S., Navaroli, D. M., Didiot, M.-C., Cardia, J., Pandarinathan, L., Alterman, J. F., Fogarty, K., Standley, C., Lifshitz, L. M., Bellve, K. D., Prot, M., Echeverria, D., Corvera, S., Khvorova, A. Tags: Chemical Biology and Nucleic Acid Chemistry Source Type: research
Topology independent comparison of RNA 3D structures using the CLICK algorithm
In this study, we extend and optimize the CLICK algorithm to superimpose pairs of RNA 3D structures and RNA–protein complexes, independent of the associated topologies. Benchmarking Rclick on four different datasets showed that it is either comparable to or better than other structural alignment methods in terms of the extent of structural overlaps. Rclick also recognizes conformational changes between RNA structures and produces complementary alignments to maximize the extent of detectable similarity. Applying Rclick to study Ribonuclease III protein correctly aligned the RNA binding sites of RNAse III with its subs...
Source: Nucleic Acids Research - January 8, 2017 Category: Research Authors: Nguyen, M. N., Sim, A. Y. L., Wan, Y., Madhusudhan, M. S., Verma, C. Tags: Computational Methods Methods Online Source Type: research
ChIA-PET2: a versatile and flexible pipeline for ChIA-PET data analysis
ChIA-PET2 is a versatile and flexible pipeline for analyzing different types of ChIA-PET data from raw sequencing reads to chromatin loops. ChIA-PET2 integrates all steps required for ChIA-PET data analysis, including linker trimming, read alignment, duplicate removal, peak calling and chromatin loop calling. It supports different kinds of ChIA-PET data generated from different ChIA-PET protocols and also provides quality controls for different steps of ChIA-PET analysis. In addition, ChIA-PET2 can use phased genotype data to call allele-specific chromatin interactions. We applied ChIA-PET2 to different ChIA-PET datasets, ...
Source: Nucleic Acids Research - January 8, 2017 Category: Research Authors: Li, G., Chen, Y., Snyder, M. P., Zhang, M. Q. Tags: Computational Methods, Chromatin and Epigenetics Methods Online Source Type: research
TALEN/CRISPR-mediated engineering of a promoterless anti-viral RNAi hairpin into an endogenous miRNA locus
Successful RNAi applications depend on strategies allowing robust and persistent expression of minimal gene silencing triggers without perturbing endogenous gene expression. Here, we propose a novel avenue which is integration of a promoterless shmiRNA, i.e. a shRNA embedded in a micro-RNA (miRNA) scaffold, into an engineered genomic miRNA locus. For proof-of-concept, we used TALE or CRISPR/Cas9 nucleases to site-specifically integrate an anti-hepatitis C virus (HCV) shmiRNA into the liver-specific miR-122/hcr locus in hepatoma cells, with the aim to obtain cellular clones that are genetically protected against HCV infecti...
Source: Nucleic Acids Research - January 8, 2017 Category: Research Authors: Senis, E., Mockenhaupt, S., Rupp, D., Bauer, T., Paramasivam, N., Knapp, B., Gronych, J., Grosse, S., Windisch, M. P., Schmidt, F., Theis, F. J., Eils, R., Lichter, P., Schlesner, M., Bartenschlager, R., Grimm, D. Tags: Targeted inhibition of gene function, Targeted gene modification Methods Online Source Type: research
COME: a robust coding potential calculation tool for lncRNA identification and characterization based on multiple features
Recent genomic studies suggest that novel long non-coding RNAs (lncRNAs) are specifically expressed and far outnumber annotated lncRNA sequences. To identify and characterize novel lncRNAs in RNA sequencing data from new samples, we have developed COME, a coding potential calculation tool based on multiple features. It integrates multiple sequence-derived and experiment-based features using a decompose–compose method, which makes it more accurate and robust than other well-known tools. We also showed that COME was able to substantially improve the consistency of predication results from other coding potential calcula...
Source: Nucleic Acids Research - January 8, 2017 Category: Research Authors: Hu, L., Xu, Z., Hu, B., Lu, Z. J. Tags: RNA characterisation and manipulation, Computational Methods Methods Online Source Type: research
Methods to increase reproducibility in differential gene expression via meta-analysis
Findings from clinical and biological studies are often not reproducible when tested in independent cohorts. Due to the testing of a large number of hypotheses and relatively small sample sizes, results from whole-genome expression studies in particular are often not reproducible. Compared to single-study analysis, gene expression meta-analysis can improve reproducibility by integrating data from multiple studies. However, there are multiple choices in designing and carrying out a meta-analysis. Yet, clear guidelines on best practices are scarce. Here, we hypothesized that studying subsets of very large meta-analyses would...
Source: Nucleic Acids Research - January 8, 2017 Category: Research Authors: Sweeney, T. E., Haynes, W. A., Vallania, F., Ioannidis, J. P., Khatri, P. Tags: Computational Methods, Genomics Methods Online Source Type: research
Division of labor among Mycobacterium smegmatis RNase H enzymes: RNase H1 activity of RnhA or RnhC is essential for growth whereas RnhB and RnhA guard against killing by hydrogen peroxide in stationary phase
We report that RnhA (like RnhC characterized previously) is an RNase H1-type magnesium-dependent endonuclease with stringent specificity for RNA:DNA hybrid duplexes. Whereas RnhA does not incise an embedded mono-ribonucleotide, it can efficiently cleave within tracts of four or more ribonucleotides in duplex DNA. We gained genetic insights to the division of labor among mycobacterial RNases H by deleting the rnhA, rnhB, rnhC and rnhD genes, individually and in various combinations. The salient conclusions are that: (i) RNase H1 activity is essential for mycobacterial growth and can be provided by either RnhC or RnhA; (ii) ...
Source: Nucleic Acids Research - January 8, 2017 Category: Research Authors: Gupta, R., Chatterjee, D., Glickman, M. S., Shuman, S. Tags: NAR Breakthrough Article Source Type: research
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Source: Nucleic Acids Research - January 8, 2017 Category: Research Tags: Front-Matter/Back-Matter Source Type: research
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Source: Nucleic Acids Research - January 8, 2017 Category: Research Tags: Front-Matter/Back-Matter Source Type: research
Nucleic Acids Research: VOLUME 45 ISSUE 1 2017
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Source: Nucleic Acids Research - January 8, 2017 Category: Research Tags: Front-Matter/Back-Matter Source Type: research
