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  • 1
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    A compendium of RNA-binding motifs for decoding gene regulation (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-07-13
    Description: RNA-binding proteins are key regulators of gene expression, yet only a small fraction have been functionally characterized. Here we report a systematic analysis of the RNA motifs recognized by RNA-binding proteins, encompassing 205 distinct genes from 24 diverse eukaryotes. The sequence specificities of RNA-binding proteins display deep evolutionary conservation, and the recognition preferences for a large fraction of metazoan RNA-binding proteins can thus be inferred from their RNA-binding domain sequence. The motifs that we identify in vitro correlate well with in vivo RNA-binding data. Moreover, we can associate them with distinct functional roles in diverse types of post-transcriptional regulation, enabling new insights into the functions of RNA-binding proteins both in normal physiology and in human disease. These data provide an unprecedented overview of RNA-binding proteins and their targets, and constitute an invaluable resource for determining post-transcriptional regulatory mechanisms in eukaryotes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929597/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929597/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ray, Debashish -- Kazan, Hilal -- Cook, Kate B -- Weirauch, Matthew T -- Najafabadi, Hamed S -- Li, Xiao -- Gueroussov, Serge -- Albu, Mihai -- Zheng, Hong -- Yang, Ally -- Na, Hong -- Irimia, Manuel -- Matzat, Leah H -- Dale, Ryan K -- Smith, Sarah A -- Yarosh, Christopher A -- Kelly, Seth M -- Nabet, Behnam -- Mecenas, Desirea -- Li, Weimin -- Laishram, Rakesh S -- Qiao, Mei -- Lipshitz, Howard D -- Piano, Fabio -- Corbett, Anita H -- Carstens, Russ P -- Frey, Brendan J -- Anderson, Richard A -- Lynch, Kristen W -- Penalva, Luiz O F -- Lei, Elissa P -- Fraser, Andrew G -- Blencowe, Benjamin J -- Morris, Quaid D -- Hughes, Timothy R -- 1R01HG00570/HG/NHGRI NIH HHS/ -- DK015602-05/DK/NIDDK NIH HHS/ -- MOP-125894/Canadian Institutes of Health Research/Canada -- MOP-14409/Canadian Institutes of Health Research/Canada -- MOP-49451/Canadian Institutes of Health Research/Canada -- MOP-67011/Canadian Institutes of Health Research/Canada -- MOP-93671/Canadian Institutes of Health Research/Canada -- P30 CA014520/CA/NCI NIH HHS/ -- R01 CA104708/CA/NCI NIH HHS/ -- R01 GM051968/GM/NIGMS NIH HHS/ -- R01 GM084034/GM/NIGMS NIH HHS/ -- R01 HG005700/HG/NHGRI NIH HHS/ -- R01GM084034/GM/NIGMS NIH HHS/ -- T32 GM008061/GM/NIGMS NIH HHS/ -- Z01 DK015602-01/Intramural NIH HHS/ -- England -- Nature. 2013 Jul 11;499(7457):172-7. doi: 10.1038/nature12311.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Donnelly Centre, University of Toronto, Toronto M5S 3E1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23846655" target="_blank"〉PubMed〈/a〉
    Keywords: Autistic Disorder/genetics ; Base Sequence ; Binding Sites/genetics ; Conserved Sequence/genetics ; Eukaryotic Cells/metabolism ; Gene Expression Regulation/*genetics ; Humans ; Molecular Sequence Data ; Nucleotide Motifs/*genetics ; Protein Structure, Tertiary/genetics ; RNA Stability/genetics ; RNA-Binding Proteins/chemistry/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Systematic discovery of structural elements governing stability of mammalian messenger RNAs (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-04-13
    Description: Decoding post-transcriptional regulatory programs in RNA is a critical step towards the larger goal of developing predictive dynamical models of cellular behaviour. Despite recent efforts, the vast landscape of RNA regulatory elements remains largely uncharacterized. A long-standing obstacle is the contribution of local RNA secondary structure to the definition of interaction partners in a variety of regulatory contexts, including--but not limited to--transcript stability, alternative splicing and localization. There are many documented instances where the presence of a structural regulatory element dictates alternative splicing patterns (for example, human cardiac troponin T) or affects other aspects of RNA biology. Thus, a full characterization of post-transcriptional regulatory programs requires capturing information provided by both local secondary structures and the underlying sequence. Here we present a computational framework based on context-free grammars and mutual information that systematically explores the immense space of small structural elements and reveals motifs that are significantly informative of genome-wide measurements of RNA behaviour. By applying this framework to genome-wide human mRNA stability data, we reveal eight highly significant elements with substantial structural information, for the strongest of which we show a major role in global mRNA regulation. Through biochemistry, mass spectrometry and in vivo binding studies, we identified human HNRPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1, also known as HNRNPA2B1) as the key regulator that binds this element and stabilizes a large number of its target genes. We created a global post-transcriptional regulatory map based on the identity of the discovered linear and structural cis-regulatory elements, their regulatory interactions and their target pathways. This approach could also be used to reveal the structural elements that modulate other aspects of RNA behaviour.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350620/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350620/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goodarzi, Hani -- Najafabadi, Hamed S -- Oikonomou, Panos -- Greco, Todd M -- Fish, Lisa -- Salavati, Reza -- Cristea, Ileana M -- Tavazoie, Saeed -- 2R01HG003219/HG/NHGRI NIH HHS/ -- DP1 DA026192/DA/NIDA NIH HHS/ -- DP1 OD003787/OD/NIH HHS/ -- DP1 OD003787-05/OD/NIH HHS/ -- R01 HG003219/HG/NHGRI NIH HHS/ -- R01 HG003219-08/HG/NHGRI NIH HHS/ -- T32-GM066699/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Apr 8;485(7397):264-8. doi: 10.1038/nature11013.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08540, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22495308" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions/genetics/physiology ; Algorithms ; Animals ; Breast Neoplasms/genetics ; Cell Line, Tumor ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Genome, Human/genetics ; Genomics ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/metabolism ; Humans ; Mice ; *Nucleic Acid Conformation ; Nucleotide Motifs ; *RNA Stability/genetics ; RNA, Messenger/chemistry/*genetics/*metabolism ; RNA, Small Interfering ; Time Factors ; Transcription, Genetic
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-12-20
    Description: To facilitate precision medicine and whole-genome annotation, we developed a machine-learning technique that scores how strongly genetic variants affect RNA splicing, whose alteration contributes to many diseases. Analysis of more than 650,000 intronic and exonic variants revealed widespread patterns of mutation-driven aberrant splicing. Intronic disease mutations that are more than 30 nucleotides from any splice site alter splicing nine times as often as common variants, and missense exonic disease mutations that have the least impact on protein function are five times as likely as others to alter splicing. We detected tens of thousands of disease-causing mutations, including those involved in cancers and spinal muscular atrophy. Examination of intronic and exonic variants found using whole-genome sequencing of individuals with autism revealed misspliced genes with neurodevelopmental phenotypes. Our approach provides evidence for causal variants and should enable new discoveries in precision medicine.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362528/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362528/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xiong, Hui Y -- Alipanahi, Babak -- Lee, Leo J -- Bretschneider, Hannes -- Merico, Daniele -- Yuen, Ryan K C -- Hua, Yimin -- Gueroussov, Serge -- Najafabadi, Hamed S -- Hughes, Timothy R -- Morris, Quaid -- Barash, Yoseph -- Krainer, Adrian R -- Jojic, Nebojsa -- Scherer, Stephen W -- Blencowe, Benjamin J -- Frey, Brendan J -- P30 CA045508/CA/NCI NIH HHS/ -- R37 GM042699/GM/NIGMS NIH HHS/ -- R37-GM42699A/GM/NIGMS NIH HHS/ -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2015 Jan 9;347(6218):1254806. doi: 10.1126/science.1254806. Epub 2014 Dec 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario M5S 3G4, Canada. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. Program on Genetic Networks and Program on Neural Computation & Adaptive Perception, Canadian Institute for Advanced Research, Toronto, Ontario M5G 1Z8, Canada. ; Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario M5S 3G4, Canada. Program on Genetic Networks and Program on Neural Computation & Adaptive Perception, Canadian Institute for Advanced Research, Toronto, Ontario M5G 1Z8, Canada. Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3G4, Canada. ; McLaughlin Centre, University of Toronto, Toronto, Ontario M5G 0A4, Canada. Centre for Applied Genomics, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. ; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. Program on Genetic Networks and Program on Neural Computation & Adaptive Perception, Canadian Institute for Advanced Research, Toronto, Ontario M5G 1Z8, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario M5S 3G4, Canada. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. Program on Genetic Networks and Program on Neural Computation & Adaptive Perception, Canadian Institute for Advanced Research, Toronto, Ontario M5G 1Z8, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario M5S 3G4, Canada. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ; eScience Group, Microsoft Research, Redmond, WA 98052, USA. ; Program on Genetic Networks and Program on Neural Computation & Adaptive Perception, Canadian Institute for Advanced Research, Toronto, Ontario M5G 1Z8, Canada. McLaughlin Centre, University of Toronto, Toronto, Ontario M5G 0A4, Canada. Centre for Applied Genomics, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. McLaughlin Centre, University of Toronto, Toronto, Ontario M5G 0A4, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario M5S 3G4, Canada. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. Program on Genetic Networks and Program on Neural Computation & Adaptive Perception, Canadian Institute for Advanced Research, Toronto, Ontario M5G 1Z8, Canada. Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3G4, Canada. McLaughlin Centre, University of Toronto, Toronto, Ontario M5G 0A4, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. eScience Group, Microsoft Research, Redmond, WA 98052, USA. frey@psi.toronto.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25525159" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics ; *Artificial Intelligence ; Child Development Disorders, Pervasive/*genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/*genetics ; Computer Simulation ; DNA/genetics ; Exons/genetics ; Genetic Code ; Genetic Markers ; Genetic Variation ; Genome-Wide Association Study/*methods ; Humans ; Introns/genetics ; Models, Genetic ; Molecular Sequence Annotation/*methods ; Muscular Atrophy, Spinal/*genetics ; Mutation, Missense ; Nuclear Proteins/genetics ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; RNA Splice Sites/genetics ; RNA Splicing/*genetics ; RNA-Binding Proteins/genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    Identification of C2H2-ZF binding preferences from ChIP-seq data using RCADE (2015)
    Oxford University Press
    Details
    Publication Date: 2015-08-25
    Description: : Current methods for motif discovery from chromatin immunoprecipitation followed by sequencing (ChIP-seq) data often identify non-targeted transcription factor (TF) motifs, and are even further limited when peak sequences are similar due to common ancestry rather than common binding factors. The latter aspect particularly affects a large number of proteins from the Cys 2 His 2 zinc finger (C2H2-ZF) class of TFs, as their binding sites are often dominated by endogenous retroelements that have highly similar sequences. Here, we present recognition code-assisted discovery of regulatory elements (RCADE) for motif discovery from C2H2-ZF ChIP-seq data. RCADE combines predictions from a DNA recognition code of C2H2-ZFs with ChIP-seq data to identify models that represent the genuine DNA binding preferences of C2H2-ZF proteins. We show that RCADE is able to identify generalizable binding models even from peaks that are exclusively located within the repeat regions of the genome, where state-of-the-art motif finding approaches largely fail. Availability and implementation: RCADE is available as a webserver and also for download at http://rcade.ccbr.utoronto.ca/ . Supplementary information: Supplementary data are available at Bioinformatics online. Contact: t.hughes@utoronto.ca
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 5
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    Global identification of conserved post-transcriptional regulatory programs in trypanosomatids (2013)
    Oxford University Press
    Details
    Publication Date: 2013-10-08
    Description: While regulatory programs are extensively studied at the level of transcription, elements that are involved in regulation of post-transcriptional processes are largely unknown, and methods for systematic identification of these elements are in early stages. Here, using a novel computational framework, we have integrated sequence information with several functional genomics data sets to characterize conserved regulatory programs of trypanosomatids, a group of eukaryotes that almost entirely rely on post-transcriptional processes for regulation of mRNA abundance. This analysis revealed a complex network of linear and structural RNA elements that potentially govern mRNA abundance across different life stages and environmental conditions. Furthermore, we show that the conserved regulatory network that we have identified is responsive to chemical perturbation of several biological functions in trypanosomatids. We have further characterized one of the most abundant regulatory RNA elements that we discovered, an AU-rich element (ARE) that can be found in 3' untranslated region of many trypanosomatid genes. Using bioinformatics approaches as well as in vitro and in vivo experiments, we have identified three ELAV-like homologs, including the developmentally critical protein Tb RBP6, which regulate abundance of a large number of trypanosomatid ARE-containing transcripts. Together, these studies lay out a roadmap for characterization of mechanisms that modulate development and metabolic pathways in trypanosomatids.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    A structural approach reveals how neighbouring C2H2 zinc fingers influence DNA binding specificity (2015)
    Oxford University Press
    Details
    Publication Date: 2015-10-31
    Description: Development of an accurate protein–DNA recognition code that can predict DNA specificity from protein sequence is a central problem in biology. C 2 H 2 zinc fingers constitute by far the largest family of DNA binding domains and their binding specificity has been studied intensively. However, despite decades of research, accurate prediction of DNA specificity remains elusive. A major obstacle is thought to be the inability of current methods to account for the influence of neighbouring domains. Here we show that this problem can be addressed using a structural approach: we build structural models for all C 2 H 2 -ZF–DNA complexes with known binding motifs and find six distinct binding modes. Each mode changes the orientation of specificity residues with respect to the DNA, thereby modulating base preference. Most importantly, the structural analysis shows that residues at the domain interface strongly and predictably influence the binding mode, and hence specificity. Accounting for predicted binding mode significantly improves prediction accuracy of predicted motifs. This new insight into the fundamental behaviour of C 2 H 2 -ZFs has implications for both improving the prediction of natural zinc finger-binding sites, and for prioritizing further experiments to complete the code. It also provides a new design feature for zinc finger engineering.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    Global identification of conserved post-transcriptional regulatory programs in trypanosomatids (2013)
    Oxford University Press
    Details
    Publication Date: 2013-07-22
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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