Person: Sliz, Piotr
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Sliz
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Piotr
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Sliz, Piotr
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Publication Development of the Precision Link Biobank at Boston Children’s Hospital: Challenges and Opportunities(MDPI, 2017) Bourgeois, Florence; Avillach, Paul; Kong, Sek Won; Heinz, Michelle M.; Tran, Tram A.; Chakrabarty, Ramkrishna; Bickel, Jonathan; Sliz, Piotr; Borglund, Erin M.; Kornetsky, Susan; Mandl, KennethIncreasingly, biobanks are being developed to support organized collections of biological specimens and associated clinical information on broadly consented, diverse patient populations. We describe the implementation of a pediatric biobank, comprised of a fully-informed patient cohort linking specimens to phenotypic data derived from electronic health records (EHR). The Biobank was launched after multiple stakeholders’ input and implemented initially in a pilot phase before hospital-wide expansion in 2016. In-person informed consent is obtained from all participants enrolling in the Biobank and provides permission to: (1) access EHR data for research; (2) collect and use residual specimens produced as by-products of routine care; and (3) share de-identified data and specimens outside of the institution. Participants are recruited throughout the hospital, across diverse clinical settings. We have enrolled 4900 patients to date, and 41% of these have an associated blood sample for DNA processing. Current efforts are focused on aligning the Biobank with other ongoing research efforts at our institution and extending our electronic consenting system to support remote enrollment. A number of pediatric-specific challenges and opportunities is reviewed, including the need to re-consent patients when they reach 18 years of age, the ability to enroll family members accompanying patients and alignment with disease-specific research efforts at our institution and other pediatric centers to increase cohort sizes, particularly for rare diseases.Publication Comparative analysis of LIN28-RNA binding sites identified at single nucleotide resolution(Taylor & Francis, 2017) Ransey, Elizabeth; Björkbom, Anders; Lelyveld, Victor; Biecek, Przemyslaw; Pantano, Lorena; Szostak, Jack; Sliz, PiotrABSTRACT It remains a formidable challenge to characterize the diverse complexes of RNA binding proteins and their targets. While crosslink and immunoprecipitation (CLIP) methods are powerful techniques that identify RNA targets on a global scale, the resolution and consistency of these methods is a matter of debate. Here we present a comparative analysis of LIN28-pre-let-7 UV-induced crosslinking using a tandem mass spectrometry (MS/MS) and deep sequencing interrogation of in vitro crosslinked complexes. Interestingly, analyses by the two methods diverge in their identification of crosslinked nucleotide identity – whereas bioinformatics and sequencing analyses suggest guanine in mammalian cells, MS/MS identifies uridine. This work suggests the need for comprehensive analysis and validation of crosslinking methodologies.Publication Collaboration gets the most out of software(eLife Sciences Publications, Ltd, 2013) Morin, Andrew; Eisenbraun, Ben; Key, Jason; Sanschagrin, Paul C; Timony, Michael; Ottaviano, Michelle; Sliz, PiotrBy centralizing many of the tasks associated with the upkeep of scientific software, SBGrid allows researchers to spend more of their time on research.Publication Pinpointing RNA-Protein Cross-Links with Site-Specific Stable Isotope-Labeled Oligonucleotides(American Chemical Society, 2015) Lelyveld, Victor S.; Björkbom, Anders; Ransey, Elizabeth; Sliz, Piotr; Szostak, JackHigh affinity RNA-protein interactions are critical to cellular function, but directly identifying the determinants of binding within these complexes is often difficult. Here, we introduce a stable isotope mass labeling technique to assign specific interacting nucleotides in an oligonucleotide-protein complex by photo-cross-linking. The method relies on generating site-specific oxygen-18-labeled phosphodiester linkages in oligonucleotides, such that covalent peptide-oligonucleotide cross-link sites arising from ultraviolet irradiation can be assigned to specific sequence positions in both RNA and protein simultaneously by mass spectrometry. Using Lin28A and a let-7 pre-element RNA, we demonstrate that mass labeling permits unambiguous identification of the cross-linked sequence positions in the RNA-protein complex.Publication Selective microRNA uridylation by Zcchc6 (TUT7) and Zcchc11 (TUT4)(Oxford University Press, 2014) Thornton, James E.; Du, Peng; Jing, Lili; Sjekloca, Ljiljana; Lin, Shuibin; Grossi, Elena; Sliz, Piotr; Zon, Leonard; Gregory, RichardRecent small RNA sequencing data has uncovered 3′ end modification of mature microRNAs (miRNAs). This non-templated nucleotide addition can impact miRNA gene regulatory networks through the control of miRNA stability or by interfering with the repression of target mRNAs. The miRNA modifying enzymes responsible for this regulation remain largely uncharacterized. Here we describe the ability for two related terminal uridyl transferases (TUTases), Zcchc6 (TUT7) and Zcchc11 (TUT4), to 3′ mono-uridylate a specific subset of miRNAs involved in cell differentiation and Homeobox (Hox) gene control. Zcchc6/11 selectively uridylates these miRNAs in vitro, and we biochemically define a bipartite sequence motif that is necessary and sufficient to confer Zcchc6/11 catalyzed uridylation. Depletion of these TUTases in cultured cells causes the selective loss of 3′ mono-uridylation of many of the same miRNAs. Upon TUTase-dependent loss of uridylation, we observe a concomitant increase in non-templated 3′ mono-adenylation. Furthermore, TUTase inhibition in Zebrafish embryos causes developmental defects and aberrant Hox expression. Our results uncover the molecular basis for selective miRNA mono-uridylation by Zcchc6/11, highlight the precise control of different 3′ miRNA modifications in cells and have implications for miRNA and Hox gene regulation during development.Publication A Grid-Enabled Web Service for Low-Resolution Crystal Structure Refinement(International Union of Crystallography, 2012) O’Donovan, Daniel J.; Stokes-Rees, Ian; Nam, Yunsun; Blacklow, Stephen; Schröder, Gunnar F.; Brunger, Axel T.; Sliz, PiotrDeformable elastic network (DEN) restraints have proved to be a powerful tool for refining structures from low-resolution X-ray crystallographic data sets. Unfortunately, optimal refinement using DEN restraints requires extensive calculations and is often hindered by a lack of access to sufficient computational resources. The DEN web service presented here intends to provide structural biologists with access to resources for running computationally intensive DEN refinements in parallel on the Open Science Grid, the US cyberinfrastructure. Access to the grid is provided through a simple and intuitive web interface integrated into the SBGrid Science Portal. Using this portal, refinements combined with full parameter optimization that would take many thousands of hours on standard computational resources can now be completed in several hours. An example of the successful application of DEN restraints to the human Notch1 transcriptional complex using the grid resource, and summaries of all submitted refinements, are presented as justification.Publication A Quick Guide to Software Licensing for the Scientist-Programmer(Public Library of Science, 2012) Morin, Andrew; Urban, Jennifer; Sliz, PiotrPublication Adapting Federated Cyberinfrastructure for Shared Data Collection Facilities in Structural Biology(International Union of Crystallography, 2012) Stokes-Rees, Ian; Levesque, Ian; Murphy, Frank V.; Yang, Wei; Deacon, Ashley; Sliz, PiotrEarly stage experimental data in structural biology is generally unmaintained and inaccessible to the public. It is increasingly believed that this data, which forms the basis for each macromolecular structure discovered by this field, must be archived and, in due course, published. Furthermore, the widespread use of shared scientific facilities such as synchrotron beamlines complicates the issue of data storage, access and movement, as does the increase of remote users. This work describes a prototype system that adapts existing federated cyberinfrastructure technology and techniques to significantly improve the operational environment for users and administrators of synchrotron data collection facilities used in structural biology. This is achieved through software from the Virtual Data Toolkit and Globus, bringing together federated users and facilities from the Stanford Synchrotron Radiation Lightsource, the Advanced Photon Source, the Open Science Grid, the SBGrid Consortium and Harvard Medical School. The performance and experience with the prototype provide a model for data management at shared scientific facilities.Publication Lipid-Protein Interactions in Double-Layered Two-Dimensional AQP0 Crystals(Nature Publishing Group, 2005) Gonen, Tamir; Cheng, Yifan; Sliz, Piotr; Hiroaki, Yoko; Fujiyoshi, Yoshinori; Harrison, Stephen; Walz, ThomasLens-specific aquaporin-0 (AQP0) functions as a specific water pore and forms the thin junctions between fibre cells. We describe a 1.9 Å resolution structure of junctional AQP0, determined by electron crystallography of double-layered two-dimensional crystals. Comparison of junctional and non-junctional AQP0 structures shows that junction formation depends on a conformational switch in an extracellular loop, which may result from cleavage of the cytoplasmic N- and C-termini. In the centre of the water pathway, the closed pore in junctional AQP0 retains only three water molecules, which are too widely spaced to form hydrogen bonds with each other. Packing interactions between AQP0 tetramers in the crystalline array are mediated by lipid molecules, which assume preferred conformations. We could therefore build an atomic model for the lipid bilayer surrounding the AQP0 tetramers, and we describe lipid-protein interactions.