IntAct (freely available at http://www.ebi.ac.uk/intact) is an open-source, open data molecular interaction database populated by data either curated from the literature or from direct data ...depositions. IntAct has developed a sophisticated web-based curation tool, capable of supporting both IMEx- and MIMIx-level curation. This tool is now utilized by multiple additional curation teams, all of whom annotate data directly into the IntAct database. Members of the IntAct team supply appropriate levels of training, perform quality control on entries and take responsibility for long-term data maintenance. Recently, the MINT and IntAct databases decided to merge their separate efforts to make optimal use of limited developer resources and maximize the curation output. All data manually curated by the MINT curators have been moved into the IntAct database at EMBL-EBI and are merged with the existing IntAct dataset. Both IntAct and MINT are active contributors to the IMEx consortium (http://www.imexconsortium.org).
The International Molecular Exchange (IMEx) consortium is an international collaboration between major public interaction data providers to share literature-curation efforts and make a nonredundant ...set of protein interactions available in a single search interface on a common website (http://www.imexconsortium.org/). Common curation rules have been developed, and a central registry is used to manage the selection of articles to enter into the dataset. We discuss the advantages of such a service to the user, our quality-control measures and our data-distribution practices.
Genome-wide association studies (GWAS) have identified over 100 loci containing single nucleotide variants (SNVs) that influence the risk of developing multiple sclerosis (MS). Most of these loci lie ...in non-coding regulatory regions of the genome that are active in immune cells and are therefore thought to modify risk by altering the expression of key immune genes. To explore this hypothesis we screened genes flanking MS-associated variants for evidence of allele specific expression (ASE) by quantifying the transcription of coding variants in linkage disequilibrium with MS-associated SNVs. In total, we were able to identify and successfully analyse 200 such coding variants (from 112 genes) in both CD4+ and CD8+ T cells from 106 MS patients and 105 controls. Fifty-six of these coding variants (from 43 genes) showed statistically significant evidence of ASE in one or both cell types. In the Lck interacting transmembrane adaptor 1 gene (LIME1), for example, we were able to show that in both cell types, the MS-associated variant rs2256814 increased the expression of some transcripts while simultaneously reducing the expression of other transcripts. In CD4+ cells from an additional independent set of 96 cases and 93 controls we were able to replicate the effect of this SNV on the balance of alternate LIME1 transcripts using qPCR (p = 5 × 10
). Our data thus indicate that some of the MS-associated SNVs identified by GWAS likely exert their effects on risk by distorting the balance of alternate transcripts rather than by changing the overall level of gene expression.
The Angelman/Prader-Willi syndrome (AS/PWS) domain contains at least 8 imprinted genes regulated by a bipartite imprinting center (IC) associated with the SNRPN gene. One component of the IC, the ...PWS-IC, governs the paternal epigenotype and expression of paternal genes. The mechanisms by which imprinting and expression of paternal genes within the AS/PWS domain - such as MKRN3 and NDN - are regulated by the PWS-IC are unclear. The syntenic region in the mouse is organized and imprinted similarly to the human domain with the murine PWS-IC defined by a 6 kb interval within the Snrpn locus that includes the promoter. To identify regulatory elements that may mediate PWS-IC function, we mapped the location and allele-specificity of DNase I hypersensitive (DH) sites within the PWS-IC in brain cells, then identified transcription factor binding sites within a subset of these DH sites. Six major paternal-specific DH sites were detected in the Snrpn gene, five of which map within the 6 kb PWS-IC. We postulate these five DH sites represent functional components of the murine PWS-IC. Analysis of transcription factor binding within multiple DH sites detected nuclear respiratory factors (NRF's) and YY1 specifically on the paternal allele. NRF's and YY1 were also detected in the paternal promoter region of the murine Mrkn3 and Ndn genes. These results suggest that NRF's and YY1 may facilitate PWS-IC function and coordinately regulate expression of paternal genes. The presence of NRF's also suggests a link between transcriptional regulation within the AS/PWS domain and regulation of respiration. 3C analyses indicated Mkrn3 lies in close proximity to the PWS-IC on the paternal chromosome, evidence that the PWS-IC functions by allele-specific interaction with its distal target genes. This could occur by allele-specific co-localization of the PWS-IC and its target genes to transcription factories containing NRF's and YY1.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Throughout history, the life sciences have been revolutionised by technological advances; in our era this is manifested by advances in instrumentation for data generation, and consequently ...researchers now routinely handle large amounts of heterogeneous data in digital formats. The simultaneous transitions towards biology as a data science and towards a 'life cycle' view of research data pose new challenges. Researchers face a bewildering landscape of data management requirements, recommendations and regulations, without necessarily being able to access data management training or possessing a clear understanding of practical approaches that can assist in data management in their particular research domain.
Here we provide an overview of best practice data life cycle approaches for researchers in the life sciences/bioinformatics space with a particular focus on 'omics' datasets and computer-based data processing and analysis. We discuss the different stages of the data life cycle and provide practical suggestions for useful tools and resources to improve data management practices.
IntAct is an open-source, open data molecular interaction database populated by data either curated from the literature or from direct data depositions. Two levels of curation are now available ...within the database, with both IMEx-level annotation and less detailed MIMIx-compatible entries currently supported. As from September 2011, IntAct contains approximately 275 000 curated binary interaction evidences from over 5000 publications. The IntAct website has been improved to enhance the search process and in particular the graphical display of the results. New data download formats are also available, which will facilitate the inclusion of IntAct's data in the Semantic Web. IntAct is an active contributor to the IMEx consortium (http://www.imexconsortium.org). IntAct source code and data are freely available at http://www.ebi.ac.uk/intact.
We conducted a genome-wide meta-analysis of cognitive empathy using the 'Reading the Mind in the Eyes' Test (Eyes Test) in 88,056 research volunteers of European Ancestry (44,574 females and 43,482 ...males) from 23andMe Inc., and an additional 1497 research volunteers of European Ancestry (891 females and 606 males) from the Brisbane Longitudinal Twin Study. We confirmed a female advantage on the Eyes Test (Cohen's d=0.21, P<2.2 × 10
), and identified a locus in 3p26.1 that is associated with scores on the Eyes Test in females (rs7641347, P
=1.58 × 10
). Common single nucleotide polymorphisms explained 5.8% (95% CI: 4.5%-7.2%; P=1.00 × 10
) of the total trait variance in both sexes, and we identified a twin heritability of 28% (95% CI: 13%-42%). Finally, we identified significant genetic correlation between the Eyes Test and anorexia nervosa, openness (NEO-Five Factor Inventory), and different measures of educational attainment and cognitive aptitude.
Several DNA binding motifs have been described in the C-terminus of histone H1 (Churchill & Travers, 1991), of these the S/TPKK repeat (Suzuki, 1989) often occurs as a part of an octapeptide repeat ...of the type XTPKKXKK. We have studied in detail the DNA and chromatin condensing properties of a consensus octapeptide KSPKKAKK (8 mer) present in many histone H1 subtypes and its imperfect repeat ATPKKSTKKTPKKAKK (16 mer TPKK) as it occurs in the C-terminus of rat histone H1d. The 16 mer TPKK peptide containing two S/TPKK motifs was able to condense both rat oligonucleosomal (2−5 kbp) DNA and histone H1-depleted chromatin as revealed by circular dichroism spectroscopy. The 8 mer peptide, however, was unable to condense either the DNA or the histone H1-depleted chromatin. Both the 8 mer peptide and the 16 mer TPKK peptide displaced distamycin A from the drug−DNA complex, although with different efficiency, indicating that while these two peptides could bind DNA, only the 16 mer (TPKK) peptide could bring about condensation of DNA and histone H1-depleted chromatin. A mutant 16 mer (TAKK) peptide wherein two proline residues are replaced by alanine, was ineffective in bringing about condensation of both DNA and histone H1-depleted chromatin. These results suggest that the two β-turn structures present in the 16 mer (TPKK) peptide could be important in facilitating binding to different regions of duplex DNA thereby bringing about close packing and condensation. The condensation property of the 16 mer (TPKK) peptide was very similar to that of histone H1 in terms of (a) its preference for AT rich DNA, (b) cooperativity of condensation, and (c) salt dependence of condensation. The 16 mer (TPKK) peptide, but not the 8 mer peptide or the 16 mer (TAKK) peptide, could form complexes with a polynucleosomal 5S DNA core resulting in retarded mobility similar to the complexes formed with histone H1 on agarose gel electrophoresis.
•VRK1 and p53 form a basal stable complex in non-damaged cells.•VRK1 interacts with the p53 DNA binding domain.•DNA-contact mutants of p53 do not disrupt the interaction.•The VRK1–p53 complex is ...activated upon UV-induced DNA damage.•P53-Thr18 phosphorylation by VRK1 is an early event in DNA damage response.
DNA damage immediate cellular response requires the activation of p53 by kinases. We found that p53 forms a basal stable complex with VRK1, a Ser–Thr kinase that responds to UV-induced DNA damage by specifically phosphorylating p53. This interaction takes place through the p53 DNA binding domain, and frequent DNA-contact mutants of p53, such as R273H, R248H or R280K, do not disrupt the complex. UV-induced DNA damage activates VRK1, and is accompanied by phosphorylation of p53 at Thr-18 before it accumulates. We propose that the VRK1–p53 basal complex is an early-warning system for immediate cellular responses to DNA damage.
VRK1physically interacts with p53 by anti bait coimmunoprecipitation (1, 2, 3, 4) VRK1physically interacts with p53 by pull down (1, 2, 3)
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