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https://www.readbyqxmd.com/read/27662573/a-broad-set-of-chromatin-factors-influences-splicing
#1
Eric Allemand, Michael P Myers, Jose Garcia-Bernardo, Annick Harel-Bellan, Adrian R Krainer, Christian Muchardt
Several studies propose an influence of chromatin on pre-mRNA splicing, but it is still unclear how widespread and how direct this phenomenon is. We find here that when assembled in vivo, the U2 snRNP co-purifies with a subset of chromatin-proteins, including histones and remodeling complexes like SWI/SNF. Yet, an unbiased RNAi screen revealed that the outcome of splicing is influenced by a much larger variety of chromatin factors not all associating with the spliceosome. The availability of this broad range of chromatin factors impacting splicing further unveiled their very context specific effect, resulting in either inclusion or skipping, depending on the exon under scrutiny...
September 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27557711/rna-sequencing-of-a-mouse-model-of-spinal-muscular-atrophy-reveals-tissue-wide-changes-in-splicing-of-u12-dependent-introns
#2
Thomas Koed Doktor, Yimin Hua, Henriette Skovgaard Andersen, Sabrina Brøner, Ying Hsiu Liu, Anna Wieckowska, Maja Dembic, Gitte Hoffmann Bruun, Adrian R Krainer, Brage Storstein Andresen
Spinal Muscular Atrophy (SMA) is a neuromuscular disorder caused by insufficient levels of the Survival of Motor Neuron (SMN) protein. SMN is expressed ubiquitously and functions in RNA processing pathways that include trafficking of mRNA and assembly of snRNP complexes. Importantly, SMA severity is correlated with decreased snRNP assembly activity. In particular, the minor spliceosomal snRNPs are affected, and some U12-dependent introns have been reported to be aberrantly spliced in patient cells and animal models...
August 23, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27530828/splicing-factor-alterations-in-cancers
#3
REVIEW
Olga Anczuków, Adrian R Krainer
Tumor-associated alterations in RNA splicing result either from mutations in splicing-regulatory elements or changes in components of the splicing machinery. This review summarizes our current understanding of the role of splicing-factor alterations in human cancers. We describe splicing-factor alterations detected in human tumors and the resulting changes in splicing, highlighting cell-type-specific similarities and differences. We review the mechanisms of splicing-factor regulation in normal and cancer cells...
September 2016: RNA
https://www.readbyqxmd.com/read/27380775/global-identification-of-hnrnp-a1-binding-sites-for-sso-based-splicing-modulation
#4
Gitte H Bruun, Thomas K Doktor, Jonas Borch-Jensen, Akio Masuda, Adrian R Krainer, Kinji Ohno, Brage S Andresen
BACKGROUND: Many pathogenic genetic variants have been shown to disrupt mRNA splicing. Besides splice mutations in the well-conserved splice sites, mutations in splicing regulatory elements (SREs) may deregulate splicing and cause disease. A promising therapeutic approach is to compensate for this deregulation by blocking other SREs with splice-switching oligonucleotides (SSOs). However, the location and sequence of most SREs are not well known. RESULTS: Here, we used individual-nucleotide resolution crosslinking immunoprecipitation (iCLIP) to establish an in vivo binding map for the key splicing regulatory factor hnRNP A1 and to generate an hnRNP A1 consensus binding motif...
2016: BMC Biology
https://www.readbyqxmd.com/read/27142120/structural-stability-of-dna-origami-nanostructures-in-the-presence-of-chaotropic-agents
#5
Saminathan Ramakrishnan, Georg Krainer, Guido Grundmeier, Michael Schlierf, Adrian Keller
DNA origami represent powerful platforms for single-molecule investigations of biomolecular processes. The required structural integrity of the DNA origami may, however, pose significant limitations regarding their applicability, for instance in protein folding studies that require strongly denaturing conditions. Here, we therefore report a detailed study on the stability of 2D DNA origami triangles in the presence of the strong chaotropic denaturing agents urea and guanidinium chloride (GdmCl) and its dependence on concentration and temperature...
May 21, 2016: Nanoscale
https://www.readbyqxmd.com/read/26701265/differentiation-of-mammary-tumors-and-reduction-in-metastasis-upon-malat1-lncrna-loss
#6
Gayatri Arun, Sarah Diermeier, Martin Akerman, Kung-Chi Chang, J Erby Wilkinson, Stephen Hearn, Youngsoo Kim, A Robert MacLeod, Adrian R Krainer, Larry Norton, Edi Brogi, Mikala Egeblad, David L Spector
Genome-wide analyses have identified thousands of long noncoding RNAs (lncRNAs). Malat1 (metastasis-associated lung adenocarcinoma transcript 1) is among the most abundant lncRNAs whose expression is altered in numerous cancers. Here we report that genetic loss or systemic knockdown of Malat1 using antisense oligonucleotides (ASOs) in the MMTV (mouse mammary tumor virus)-PyMT mouse mammary carcinoma model results in slower tumor growth accompanied by significant differentiation into cystic tumors and a reduction in metastasis...
January 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/26655495/antisense-oligonucleotide-directed-inhibition-of-nonsense-mediated-mrna-decay
#7
Tomoki T Nomakuchi, Frank Rigo, Isabel Aznarez, Adrian R Krainer
Nonsense-mediated mRNA decay (NMD) is a cellular quality-control mechanism that is thought to exacerbate the phenotype of certain pathogenic nonsense mutations by preventing the expression of semi-functional proteins. NMD also limits the efficacy of read-through compound (RTC)-based therapies. Here, we report a gene-specific method of NMD inhibition using antisense oligonucleotides (ASOs) and combine this approach with an RTC to effectively restore the expression of full-length protein from a nonsense-mutant allele...
February 2016: Nature Biotechnology
https://www.readbyqxmd.com/read/26490253/the-spliceosome-a-potential-achilles-heel-of-myc-driven-tumors
#8
Olga Anczuków, Adrian R Krainer
Alterations in RNA splicing are frequent in human tumors. Two recent studies of lymphoma and breast cancer have identified components of the spliceosome - the core splicing machinery - that are essential for malignant transformation driven by the transcription factor MYC. These findings provide a direct link between MYC and RNA splicing deregulation, and raise the exciting possibility of targeting spliceosome components in MYC-driven tumors.
October 22, 2015: Genome Medicine
https://www.readbyqxmd.com/read/26276636/crispr-inversion-of-ctcf-sites-alters-genome-topology-and-enhancer-promoter-function
#9
Ya Guo, Quan Xu, Daniele Canzio, Jia Shou, Jinhuan Li, David U Gorkin, Inkyung Jung, Haiyang Wu, Yanan Zhai, Yuanxiao Tang, Yichao Lu, Yonghu Wu, Zhilian Jia, Wei Li, Michael Q Zhang, Bing Ren, Adrian R Krainer, Tom Maniatis, Qiang Wu
CTCF and the associated cohesin complex play a central role in insulator function and higher-order chromatin organization of mammalian genomes. Recent studies identified a correlation between the orientation of CTCF-binding sites (CBSs) and chromatin loops. To test the functional significance of this observation, we combined CRISPR/Cas9-based genomic-DNA-fragment editing with chromosome-conformation-capture experiments to show that the location and relative orientations of CBSs determine the specificity of long-range chromatin looping in mammalian genomes, using protocadherin (Pcdh) and β-globin as model genes...
August 13, 2015: Cell
https://www.readbyqxmd.com/read/26047612/differential-connectivity-of-splicing-activators-and-repressors-to-the-human-spliceosome
#10
Martin Akerman, Oliver I Fregoso, Shipra Das, Cristian Ruse, Mads A Jensen, Darryl J Pappin, Michael Q Zhang, Adrian R Krainer
BACKGROUND: During spliceosome assembly, protein-protein interactions (PPI) are sequentially formed and disrupted to accommodate the spatial requirements of pre-mRNA substrate recognition and catalysis. Splicing activators and repressors, such as SR proteins and hnRNPs, modulate spliceosome assembly and regulate alternative splicing. However, it remains unclear how they differentially interact with the core spliceosome to perform their functions. RESULTS: Here, we investigate the protein connectivity of SR and hnRNP proteins to the core spliceosome using probabilistic network reconstruction based on the integration of interactome and gene expression data...
2015: Genome Biology
https://www.readbyqxmd.com/read/25780112/splicing-still-so-much-to-learn
#11
Adrian R Krainer
No abstract text is available yet for this article.
April 2015: RNA
https://www.readbyqxmd.com/read/25645699/rescue-of-gene-expression-changes-in-an-induced-mouse-model-of-spinal-muscular-atrophy-by-an-antisense-oligonucleotide-that-promotes-inclusion-of-smn2-exon-7
#12
John F Staropoli, Huo Li, Seung J Chun, Norm Allaire, Patrick Cullen, Alice Thai, Christina M Fleet, Yimin Hua, C Frank Bennett, Adrian R Krainer, Doug Kerr, Alexander McCampbell, Frank Rigo, John P Carulli
Spinal muscular atrophy (SMA) is a neuromuscular disease caused by disruption of the survival motor neuron 1 (SMN1) gene, partly compensated for by the paralogous gene SMN2. Exon 7 inclusion is critical for full-length SMN protein production and occurs at a much lower frequency for SMN2 than for SMN1. Antisense oligonucleotide (ASO)-mediated blockade of an intron 7 splicing silencer was previously shown to promote inclusion of SMN2 exon 7 in SMA mouse models and mediate phenotypic rescue. However, downstream molecular consequences of this ASO therapy have not been defined...
April 2015: Genomics
https://www.readbyqxmd.com/read/25583329/motor-neuron-cell-nonautonomous-rescue-of-spinal-muscular-atrophy-phenotypes-in-mild-and-severe-transgenic-mouse-models
#13
Yimin Hua, Ying Hsiu Liu, Kentaro Sahashi, Frank Rigo, C Frank Bennett, Adrian R Krainer
Survival of motor neuron (SMN) deficiency causes spinal muscular atrophy (SMA), but the pathogenesis mechanisms remain elusive. Restoring SMN in motor neurons only partially rescues SMA in mouse models, although it is thought to be therapeutically essential. Here, we address the relative importance of SMN restoration in the central nervous system (CNS) versus peripheral tissues in mouse models using a therapeutic splice-switching antisense oligonucleotide to restore SMN and a complementary decoy oligonucleotide to neutralize its effects in the CNS...
February 1, 2015: Genes & Development
https://www.readbyqxmd.com/read/25525159/rna-splicing-the-human-splicing-code-reveals-new-insights-into-the-genetic-determinants-of-disease
#14
Hui Y Xiong, Babak Alipanahi, Leo J Lee, Hannes Bretschneider, Daniele Merico, Ryan K C Yuen, Yimin Hua, Serge Gueroussov, Hamed S Najafabadi, Timothy R Hughes, Quaid Morris, Yoseph Barash, Adrian R Krainer, Nebojsa Jojic, Stephen W Scherer, Benjamin J Blencowe, Brendan J Frey
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...
January 9, 2015: Science
https://www.readbyqxmd.com/read/25418731/dazl-limits-pluripotency-differentiation-and-apoptosis-in-developing-primordial-germ-cells
#15
Hsu-Hsin Chen, Maaike Welling, Donald B Bloch, Javier Muñoz, Edwin Mientjes, Xinjie Chen, Cody Tramp, Jie Wu, Akiko Yabuuchi, Yu-Fen Chou, Christa Buecker, Adrian Krainer, Rob Willemsen, Albert J Heck, Niels Geijsen
The scarcity of primordial germ cells (PGCs) in the developing mammalian embryo hampers robust biochemical analysis of the processes that underlie early germ cell formation. Here, we demonstrate that DAZL, a germ cell-specific RNA binding protein, is a robust PGC marker during in vitro germ cell development. Using Dazl-GFP reporter ESCs, we demonstrate that DAZL plays a central role in a large mRNA/protein interactive network that blocks the translation of core pluripotency factors, including Sox2 and Sall4, as well as of Suz12, a polycomb family member required for differentiation of pluripotent cells...
November 11, 2014: Stem Cell Reports
https://www.readbyqxmd.com/read/25416801/hiv-1-transcription-is-regulated-by-splicing-factor-srsf1
#16
Sean Paz, Adrian R Krainer, Massimo Caputi
Efficient transcription of the HIV-1 genome is regulated by Tat, which recruits P-TEFb from the 7SK small nuclear ribonucleoprotein (snRNP) and other nucleoplasmic complexes to phosphorylate RNA polymerase II and other factors associated with the transcription complex. Although Tat activity is dependent on its binding to the viral TAR sequence, little is known about the cellular factors that might also assemble onto this region of the viral transcript. Here, we report that the splicing factor SRSF1 (SF2/ASF) and Tat recognize overlapping sequences within TAR and the 7SK RNA...
December 16, 2014: Nucleic Acids Research
https://www.readbyqxmd.com/read/25074920/p53%C3%AE-is-a-transcriptionally-inactive-p53-isoform-able-to-reprogram-cells-toward-a-metastatic-like-state
#17
Serif Senturk, Zhan Yao, Matthew Camiolo, Brendon Stiles, Trushar Rathod, Alice M Walsh, Alice Nemajerova, Matthew J Lazzara, Nasser K Altorki, Adrian Krainer, Ute M Moll, Scott W Lowe, Luca Cartegni, Raffaella Sordella
Although much is known about the underlying mechanisms of p53 activity and regulation, the factors that influence the diversity and duration of p53 responses are not well understood. Here we describe a unique mode of p53 regulation involving alternative splicing of the TP53 gene. We found that the use of an alternative 3' splice site in intron 6 generates a unique p53 isoform, dubbed p53Ψ. At the molecular level, p53Ψ is unable to bind to DNA and does not transactivate canonical p53 target genes. However, like certain p53 gain-of-function mutants, p53Ψ attenuates the expression of E-cadherin, induces expression of markers of the epithelial-mesenchymal transition, and enhances the motility and invasive capacity of cells through a unique mechanism involving the regulation of cyclophilin D activity, a component of the mitochondrial inner pore permeability...
August 12, 2014: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/24807918/emerging-functions-of-srsf1-splicing-factor-and-oncoprotein-in-rna-metabolism-and-cancer
#18
REVIEW
Shipra Das, Adrian R Krainer
Serine/Arginine Splicing Factor 1 (SRSF1) is the archetype member of the SR protein family of splicing regulators. Since its discovery over two decades ago, SRSF1 has been repeatedly surprising and intriguing investigators by the plethora of complex biologic pathways it regulates. These include several key aspects of mRNA metabolism, such as mRNA splicing, stability, and translation, as well as other mRNA-independent processes, such as miRNA processing, protein sumoylation, and the nucleolar stress response...
September 2014: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/24784568/pharmacology-of-a-central-nervous-system-delivered-2-o-methoxyethyl-modified-survival-of-motor-neuron-splicing-oligonucleotide-in-mice-and-nonhuman-primates
#19
COMPARATIVE STUDY
Frank Rigo, Seung J Chun, Daniel A Norris, Gene Hung, Sam Lee, John Matson, Robert A Fey, Hans Gaus, Yimin Hua, John S Grundy, Adrian R Krainer, Scott P Henry, C Frank Bennett
Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by the loss of survival of motor neuron (SMN) protein. Previously, we demonstrated that ISIS 396443, an antisense oligonucleotide (ASO) targeted to the SMN2 pre-mRNA, is a potent inducer of SMN2 exon 7 inclusion and SMN protein expression, and improves function and survival of mild and severe SMA mouse models. Here, we demonstrate that ISIS 396443 is the most potent ASO in central nervous system (CNS) tissues of adult mice, compared with several other chemically modified ASOs...
July 2014: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/24613350/hits-clip-and-integrative-modeling-define-the-rbfox-splicing-regulatory-network-linked-to-brain-development-and-autism
#20
Sebastien M Weyn-Vanhentenryck, Aldo Mele, Qinghong Yan, Shuying Sun, Natalie Farny, Zuo Zhang, Chenghai Xue, Margaret Herre, Pamela A Silver, Michael Q Zhang, Adrian R Krainer, Robert B Darnell, Chaolin Zhang
The RNA binding proteins Rbfox1/2/3 regulate alternative splicing in the nervous system, and disruption of Rbfox1 has been implicated in autism. However, comprehensive identification of functional Rbfox targets has been challenging. Here, we perform HITS-CLIP for all three Rbfox family members in order to globally map, at a single-nucleotide resolution, their in vivo RNA interaction sites in the mouse brain. We find that the two guanines in the Rbfox binding motif UGCAUG are critical for protein-RNA interactions and crosslinking...
March 27, 2014: Cell Reports
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