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Perturbation of Chromatin Structure Globally Affects Localization And Perturbation of Chromatin Structure Globally Affects Localization and Recruitment of Splicing Factors Ignacio Schor, David Llères, Guillermo Risso, Andrea Pawellek, Jernej Ule, Angus Lamond, Alberto Kornblihtt To cite this version: Ignacio Schor, David Llères, Guillermo Risso, Andrea Pawellek, Jernej Ule, et al.. Perturbation of Chromatin Structure Globally Affects Localization and Recruitment of Splicing Factors. PLoS ONE, Public Library of Science, 2012, 7 (11), pp.e48084. 10.1371/journal.pone.0048084. hal-03027051 HAL Id: hal-03027051 https://hal.archives-ouvertes.fr/hal-03027051 Submitted on 26 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License Perturbation of Chromatin Structure Globally Affects Localization and Recruitment of Splicing Factors Ignacio E. Schor1.¤a, David Lle`res2.¤b, Guillermo J. Risso1, Andrea Pawellek2, Jernej Ule3, Angus I. Lamond2, Alberto R. Kornblihtt1* 1 Laboratorio de Fisiologı´a y Biologı´a Molecular, Departamento de Fisiologı´a, Biologı´a Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Instituto de Fisiologı´a, Biologı´a Molecular y Neurociencias, Consejo Nacional de Investigaciones Cientı´ficas y Te´cnicas, Buenos Aires, Argentina, 2 Dundee Centre for Gene Regulation and Expression, University of Dundee, Dundee, Scotland, United Kingdom, 3 Laboratory of Molecular Biology, Medical Research Council, Cambridge, England, United Kingdom Abstract Chromatin structure is an important factor in the functional coupling between transcription and mRNA processing, not only by regulating alternative splicing events, but also by contributing to exon recognition during constitutive splicing. We observed that depolarization of neuroblastoma cell membrane potential, which triggers general histone acetylation and regulates alternative splicing, causes a concentration of SR proteins in nuclear speckles. This prompted us to analyze the effect of chromatin structure on splicing factor distribution and dynamics. Here, we show that induction of histone hyper- acetylation results in the accumulation in speckles of multiple splicing factors in different cell types. In addition, a similar effect is observed after depletion of the heterochromatic protein HP1a, associated with repressive chromatin. We used advanced imaging approaches to analyze in detail both the structural organization of the speckle compartment and nuclear distribution of splicing factors, as well as studying direct interactions between splicing factors and their association with chromatin in vivo. The results support a model where perturbation of normal chromatin structure decreases the recruitment efficiency of splicing factors to nascent RNAs, thus causing their accumulation in speckles, which buffer the amount of free molecules in the nucleoplasm. To test this, we analyzed the recruitment of the general splicing factor U2AF65 to nascent RNAs by iCLIP technique, as a way to monitor early spliceosome assembly. We demonstrate that indeed histone hyper- acetylation decreases recruitment of U2AF65 to bulk 39 splice sites, coincident with the change in its localization. In addition, prior to the maximum accumulation in speckles, ,20% of genes already show a tendency to decreased binding, while U2AF65 seems to increase its binding to the speckle-located ncRNA MALAT1. All together, the combined imaging and biochemical approaches support a model where chromatin structure is essential for efficient co-transcriptional recruitment of general and regulatory splicing factors to pre-mRNA. Citation: Schor IE, Lle`res D, Risso GJ, Pawellek A, Ule J, et al. (2012) Perturbation of Chromatin Structure Globally Affects Localization and Recruitment of Splicing Factors. PLoS ONE 7(11): e48084. doi:10.1371/journal.pone.0048084 Editor: Laszlo Tora, Institute of Genetics and Molecular and Cellular Biology, France Received June 13, 2012; Accepted September 19, 2012; Published November 12, 2012 Copyright: ß 2012 Schor et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by Argentina (PICT2010-0202, URL: http://www.agencia.gov.ar/), the University of Buenos Aires (UBACYT-X112, URL: http:// www.uba.ar/), Consejo Nacional de Investigaciones Cientı´ficas y Te´cnicas of Argentina (CONICET) (no number, URL: http://www.conicet.gov.ar/web/conicet/ inicio), Howard Hughes Medical Institute (no number, URL: http://www.hhmi.org/) and the European Alternative Splicing Network (EURASNET, European Union Network of Excellence # 518238, URL: http://www.eurasnet.info/). Grants were provided to J.U. by the Medical Research Council (U105185858, URL: http://www. mrc.ac.uk/index.htm). Grants to A.I.L. were provided by Wellcome Trust (073980/Z/03/B, URL: http://www.hhmi.org/). The Scottish Universities Life Sciences Alliance (SULSA, URL: http://www.sulsa.ac.uk/) supports the use of OMX microscope. Consejo Nacional de Investigaciones Cientı´ficas y Te´cnicas of Argentina (CONICET, URL: http://www.conicet.gov.ar/web/conicet/inicio) funded a post-doctoral fellowship for I.E.S. and funds a doctoral fellowship for G.R. European Molecular Biology Organization (EMBO, URL: http://www.embo.org/) funded a short-term fellowship for I.E.S. International Union of Biochemistry and Molecular Biology (IUBMB, URL: http://www.iubmb.org/) funded a Wood-Whelan fellowhsip for I.E.S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] . These authors contributed equally to this work. ¤a Current address: Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany ¤b Current address: Institut de Ge´ne´tique Mole´culaire de Montpellier, Centre national de la recherche scientifique, Universite´ Montpellier I & II, Montpellier, France Introduction between the transcription of genes to form nascent pre-mRNA and the simultaneous processing of these nascent transcripts into Several molecular events related to the flow of the genetic mature mRNA [1,2,3,4]. information occur in the eukaryotic nucleus. These events depend All steps of pre-mRNA processing, including capping, splicing on the interplay between proteins and nucleic acids that do not act and cleavage/poly-adenylation, are known to occur co-transcrip- in isolation from other molecules, but generally associate in large tionally [5,6], although to a different degree depending on the complexes that harbor many molecular functions. In this way gene. In the case of splicing, organisms as divergent as mammals distinct steps in nuclear processes can be coupled with each other, and yeasts show splicing factor recruitment as soon as their thereby increasing efficiency. A relevant example is the coupling binding sites in the pre-mRNA have been transcribed [7,8,9]. PLOS ONE | www.plosone.org 1 November 2012 | Volume 7 | Issue 11 | e48084 Splicing Factors and Chromatin Structure Such co-transcriptional RNA processing is, however, not strict, [39,42], suggesting a selective pressure which may act to ensure especially considering that the sequence heterogeneity of splice recognition of difficult exons in the large intron environment of sites found in mammals implies a high variability of recruitment many mammalian genes. Despite this accumulated evidence on efficiencies. The presence of splice sites whose sequences fall apart the influence of chromatin on splicing, no study assessing the from the consensus or are partially obstructed by RNA secondary relevance of chromatin structure on the general function of structures can allow alternative splicing events [10,11]. However, splicing factors has been conducted so far. many constitutive exons also have seemingly weak splice sites, Here, we report that relaxation of chromatin structure, implying that other factors are needed for their efficient definition. promoted by different treatments in several mammalian cell lines, These extra factors that participate in both constitutive and consistently results in depletion of pre-mRNA splicing factors from alternative splicing are typically auxiliary proteins (trans acting nucleoplasm and accumulation in nuclear speckles. We demon- factors), such as serine-arginine rich (SR) proteins that bind to strate that this nuclear redistribution is due to general impairment sequences in the pre-mRNA (cis elements known as splicing of splicing function and not caused by global transcription enhancers or splicing silencers) [12,13,14]. inhibition or post-translational modification of the splicing factors. Nuclear architecture is another important factor contributing to Based on the fact that chromatin relaxation does not affect the efficiency and specificity of nuclear
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