{"id":68727,"date":"2024-07-02T10:00:00","date_gmt":"2024-07-02T08:00:00","guid":{"rendered":"https:\/\/www.embl.org\/news\/?p=68727"},"modified":"2024-07-31T11:57:44","modified_gmt":"2024-07-31T09:57:44","slug":"iit-embl-new-molecules-to-modulate-gene-expression","status":"publish","type":"post","link":"https:\/\/www.embl.org\/news\/science-technology\/iit-embl-new-molecules-to-modulate-gene-expression\/","title":{"rendered":"IIT-EMBL: New molecules to modulate gene expression"},"content":{"rendered":"\n<article class=\"vf-card vf-card--brand vf-card--bordered vf-u-margin__bottom--800\" default>\n  <div class=\"vf-card__content | vf-stack vf-stack--400\">\n      <h3 class=\"vf-card__heading\">\n      Summary    <\/h3>\n                <p class=\"vf-card__text\"><ul>\r\n<li>The correct functioning of cells relies heavily on the ability to finely control gene expression.\r\n<\/li><li>Researchers at the Istituto Italiano di Tecnologia (IIT) in Genoa and the European Molecular Biology Laboratory (EMBL) in Grenoble have unveiled how gene expression can be modulated using small molecules.\r\n<\/li><li>The study focused on splicing, one of the key levels of control in gene expression that enables functional RNA versions to act as a set of instructions to produce proteins, or directly as regulators of various cellular processes.\r\n<\/li><li>These results lay the groundwork for the future identification of potential drugs that act directly on genetic mutations or modifications responsible for the onset of tumours or genetic diseases.\r\n<\/li><\/ul><\/p>\n      <\/div>\n<\/article>\n\n\n\n\n<p><em>EMBL- IIT Joint press release<\/em><\/p>\n\n\n\n<p>The correct functioning of cells relies heavily on the ability to finely control gene expression, a complex process by which the information contained in DNA is copied into RNA to eventually give rise to all the proteins and most of the regulatory molecules in the cell. If DNA can be imagined as a dense technical manual, gene expression is the method by which the cell extracts useful information from it.&nbsp;<\/p>\n\n\n\n<p>Researchers at the Istituto Italiano di Tecnologia (IIT) in Genoa and the European Molecular Biology Laboratory (EMBL) in Grenoble have unveiled how this process can be modulated using small molecules. The study lays the groundwork for the future identification of potential drugs that act directly on genetic mutations or modifications which alter the process of gene expression, thereby targeting the onset of tumours or genetic diseases.<\/p>\n\n\n\n<p>The research paper, <a href=\"https:\/\/www.nature.com\/articles\/s41467-024-48697-0\">published in <em>Nature Communications<\/em><\/a>, was coordinated by Marco De Vivo, Principal Investigator of the Molecular Modeling &amp; Drug Discovery Lab and Associate Director for Computation at IIT in Genoa, and by Marco Marcia, Group Leader at EMBL Grenoble. The results were achieved by integrating EMBL\u2019s and the <a href=\"https:\/\/www.embl.org\/partnerships\/local\/structural-biology\/\">Partnership for Structural Biology<\/a>\u2019s expertise in biochemistry, biophysics, and structural biology, and using the automated MASSIF-1 beamline jointly operated by EMBL and the <a href=\"https:\/\/www.esrf.fr\/home.html\">European Radiation Synchrotron Facility<\/a> (ESRF) to deliver X-ray photographs of the process. This was combined with expertise in computational simulation from IIT, which allowed for the study of the physico-chemical interactions of the molecules involved.<\/p>\n\n\n\n<p>The study focused on splicing \u2013 one of the key levels of control in the gene expression process. Splicing, as the name suggests, is a process by which molecular machines in the cell &#8216;cut and paste&#8217; specific sequences of RNA to create functional versions. These &#8216;mature&#8217; RNA versions then perform various functions in the cell, including acting as a set of instructions to produce proteins, or directly as regulators of various cellular processes.<\/p>\n\n\n\n<p>\u201cStudying the RNA splicing process is very complex due to the chemical reactions and the molecular actors involved, such as RNA, proteins, ions, and water molecules. Thanks to modern molecular simulation techniques, we have acquired a detailed understanding of what happens, and how to intervene to modulate splicing. Our study has already enabled us to synthesise new drug-like molecules capable of modulating splicing in a new, specific, and highly effective way,\u201d commented Marco De Vivo.<\/p>\n\n\n\n<p>Indeed, IIT and EMBL researchers, with the support of EMBLEM \u2013 EMBL\u2019s technology and knowledge transfer branch \u2013 and IIT\u2019s patent office, have recently also deposited a patent that describes novel chemical compounds acting as splicing modulators. In the future, by further improving these compounds, it may become possible to regulate the production of specific proteins linked to defective or mutated genes.<\/p>\n\n\n\n<p>\u201cVisualising splicing modulation at the near-atomic level is breathtaking. It allows us to control one of the most fundamental reactions in life. In the future, we will consolidate the successful integration of our biological experimental studies with the chemical and computational studies of our collaborators, aiming at an ambitious goal: to develop new drugs, such as antibacterials and antitumor agents,\u201d said Marco Marcia.<\/p>\n\n\n\n<p>The research is also part of IIT\u2019s RNA flagship initiative dedicated to the development and application of new RNA-based technologies.<\/p>\n\n\n\n<hr class=\"vf-divider\"\/>\n\n\n\n<h1 class=\"wp-block-heading\" id=\"Italian\"><strong>IIT-EMBL: Nuove molecole per modulare l\u2019espressione dei geni<\/strong><\/h1>\n\n\n\n<h2 class=\"wp-block-heading\">Il lavoro pubblicato su <em>Nature Communications<\/em> pone le basi per lo sviluppo di nuovi farmaci specifici per mutazioni o alterazioni genetiche alla base dell\u2019insorgenza di tumori o malattie genetiche<\/h2>\n\n\n\n<article class=\"vf-card vf-card--brand vf-card--bordered vf-u-margin__bottom--800\" default>\n  <div class=\"vf-card__content | vf-stack vf-stack--400\">\n      <h3 class=\"vf-card__heading\">\n      Sintesi    <\/h3>\n                <p class=\"vf-card__text\"><ul>\r\n<li>Il corretto funzionamento delle cellule dipende in larga misura dalla capacit\u00e0 di controllare l\u2019espressione dei geni.\r\n<\/li><li>I ricercatori dell\u2019Istituto Italiano di Tecnologia (IIT) di Genova, e del Laboratorio Europeo di Biologia Molecolare (EMBL) di Grenoble hanno svelato come l\u2019espressione dei geni pu\u00f2 essere modulata utilizzando piccole molecole.\r\n<\/li><li>Lo studio si \u00e8 concentrato sullo splicing, uno dei livelli chiave di controllo dell&#8217;espressione genica, che consente alle versioni funzionali dell&#8217;RNA di agire come un insieme di istruzioni per produrre proteine o direttamente come regolatori di vari processi cellulari.\r\n<\/li><li>Questi risultati pongono le basi per l\u2019individuazione in futuro di potenziali farmaci che agiscano direttamente sulle mutazioni o modificazioni genetiche responsabili dell&#8217;insorgenza di tumori o malattie genetiche.\r\n<\/li><\/ul><\/p>\n      <\/div>\n<\/article>\n\n\n\n\n<p>Il corretto funzionamento delle cellule dipende in larga misura dalla capacit\u00e0 di controllare l\u2019espressione dei geni &#8211; un processo complesso attraverso il quale le informazioni contenute nel DNA vengono copiate nell&#8217;RNA per dare origine a tutte le proteine e alla maggior parte delle molecole regolatrici della cellula. Se immaginiamo il DNA come un voluminoso manuale tecnico, l&#8217;espressione genica \u00e8 il metodo con cui la cellula estrae da esso le informazioni utili.<\/p>\n\n\n\n<p>I ricercatori dell\u2019Istituto Italiano di Tecnologia (IIT) di Genova, e del Laboratorio Europeo di Biologia Molecolare (EMBL) di Grenoble hanno svelato le modalit\u00e0 con questo processo pu\u00f2 essere modulato utilizzando piccole molecole. Lo studio pone le basi per l\u2019individuazione in futuro di possibili farmaci che agiscano direttamente su mutazioni o modificazioni genetiche che alterano il processo di espressione dei geni, intervenendo cos\u00ec sull\u2019insorgenza di tumori o malattie genetiche.<\/p>\n\n\n\n<p>Il lavoro di ricerca \u00e8 stato <a href=\"https:\/\/www.nature.com\/articles\/s41467-024-48697-0\">pubblicato su <em>Nature Communications<\/em><\/a> ed \u00e8 stato coordinato da Marco De Vivo, Principal Investigator del Molecular Modeling &amp; Drug Discovery Lab e Associate Director per la Computazione dell\u2019IIT a Genova, e da Marco Marcia, Group Leader all\u2019EMBL di Grenoble.<\/p>\n\n\n\n<p>Il risultato \u00e8 stato ottenuto sfruttando le competenze dell\u2019EMBL e della <a href=\"https:\/\/www.embl.org\/partnerships\/local\/structural-biology\/\">Partnership per la Biologia Strutturale<\/a> di Grenoble in biochimica, biofisica e biologia strutturale, attraverso cui si sono ottenute delle fotografie a raggi-X del processo; lo strumento utilizzato \u00e8 stato la beamline altamente automatizzata MASSIF-1, dell\u2019EMBL e dello <a href=\"https:\/\/www.esrf.fr\/home.html\">European Radiation Synchrotron Facility<\/a> (ESRF). Queste competenze sono state integrate da quelle di simulazione computazionale dell\u2019IIT, grazie a cui \u00e8 stato possibile studiare i dettagli delle interazioni chimico-fisiche tra le molecole coinvolte.<\/p>\n\n\n\n<p>Lo studio si \u00e8 concentrato sullo <em>splicing<\/em>, uno dei livelli chiave di controllo del processo di espressione genica. Lo <em>splicing<\/em> \u00e8 un processo mediante il quale le macchine molecolari nella cellula &#8220;tagliano e incollano&#8221; sequenze specifiche di RNA per crearne versioni funzionali. Queste versioni &#8220;mature&#8221; dell&#8217;RNA svolgono varie funzioni nella cellula, tra cui quella di fungere da istruzioni per la produzione di proteine o direttamente da regolatori di vari processi cellulari.&nbsp; .<\/p>\n\n\n\n<p>\u201cStudiare la reazione di splicing dell\u2019RNA, ovvero il \u201ctaglia e cuci\u201d, \u00e8 molto complesso sia per le reazioni chimiche che per gli attori molecolari coinvolti, quali l\u2019RNA, le proteine, gli ioni e le molecole di acqua. Grazie a tecniche moderne di simulazione molecolare abbiamo ottenuto una comprensione dettagliata di quello che accade, e di come si puo\u2019 intervenire per modulare lo splicing. Il nostro studio ci ha gia\u2019 permesso di sintetizzare nuove molecole simili a farmaci in grado di modulare lo splicing in un nuovo modo, specifico e molto efficace\u201d \u2013 commenta Marco De Vivo.<\/p>\n\n\n\n<p>Infatti, i ricercatori dell\u2019IIT e dell\u2019EMBL, con il supporto di<a href=\"https:\/\/embl-em.de\/\"> EMBLEM<\/a> \u2013 l\u2019ufficio dell\u2019EMBL dedicato al trasferimento di tecnologia \u2013 e dell\u2019ufficio brevetti dell\u2019IIT, hanno anche depositato un brevetto che descrive nuovi composti chimici modulatori dello splicing. In futuro, migliorando ulteriormente tali composti potrebbe diventare possibile modulare la produzione di proteine che originano da geni difettosi o mutati.<\/p>\n\n\n\n<p>\u201cVisualizzare a livello atomico la modulazione dello splicing \u00e8 emozionante. Ci permette di controllare una delle reazioni fondamentali che permettono la vita. In futuro, continuando ad integrare i nostri studi biologici sperimentali, con quelli chimici e computazionali dei nostri collaboratori, mireremo ad un obiettivo ambizioso, quello di sviluppare nuovi farmaci antibatterici e antitumorali\u201d \u2013 dice Marco Marcia.<\/p>\n\n\n\n<p>La ricerca aderisce anche all\u2019iniziativa RNA Flagship dell\u2019Istituto Italiano di Tecnologia dedicata allo sviluppo e all\u2019applicazione di nuove tecnologie a base di RNA.<\/p>\n\n\n\n<hr class=\"vf-divider\"\/>\n\n\n\n<h1 class=\"wp-block-heading\" id=\"French\"><strong>IIT-EMBL: De nouvelles mol\u00e9cules pour moduler l&#8217;expression des g\u00e8nes<\/strong><\/h1>\n\n\n\n<h2 class=\"wp-block-heading\">Les travaux publi\u00e9s dans <em>Nature Communications<\/em> posent les fondements du d\u00e9veloppement de nouveaux m\u00e9dicaments sp\u00e9cifiques aux mutations ou alt\u00e9rations g\u00e9n\u00e9tiques responsables de l&#8217;apparition de tumeurs ou de maladies g\u00e9n\u00e9tiques<\/h2>\n\n\n\n<article class=\"vf-card vf-card--brand vf-card--bordered vf-u-margin__bottom--800\" default>\n  <div class=\"vf-card__content | vf-stack vf-stack--400\">\n      <h3 class=\"vf-card__heading\">\n      R\u00e9sum\u00e9    <\/h3>\n                <p class=\"vf-card__text\"><ul>\r\n<li>Le bon fonctionnement des cellules d\u00e9pend fortement de la capacit\u00e9 \u00e0 contr\u00f4ler finement l&#8217;expression des g\u00e8nes.\r\n<\/li><li>Des chercheurs de l&#8217;Istituto Italiano di Tecnologia (IIT) de G\u00eanes et du Laboratoire europ\u00e9en de biologie mol\u00e9culaire (EMBL) de Grenoble ont d\u00e9voil\u00e9 comment l&#8217;expression des g\u00e8nes peut \u00eatre modul\u00e9e \u00e0 l&#8217;aide de petites mol\u00e9cules.\r\n<\/li><li>L&#8217;\u00e9tude s&#8217;est concentr\u00e9e sur l&#8217;\u00e9pissage, l&#8217;un des principaux niveaux de contr\u00f4le de l&#8217;expression g\u00e9n\u00e9tique qui permet aux versions fonctionnelles de l&#8217;ARN d&#8217;agir comme un ensemble d&#8217;instructions pour produire des prot\u00e9ines, ou directement comme des r\u00e9gulateurs de divers processus cellulaires.\r\n<\/li><li>Ces r\u00e9sultats posent les fondements de l&#8217;identification future de potentiels m\u00e9dicaments agissant directement sur les mutations ou les modifications g\u00e9n\u00e9tiques responsables de l&#8217;apparition de tumeurs ou de maladies g\u00e9n\u00e9tiques.<\/li><\/ul><\/p>\n      <\/div>\n<\/article>\n\n\n\n\n<p>Le bon fonctionnement des cellules d\u00e9pend fortement de la capacit\u00e9 \u00e0 contr\u00f4ler finement l&#8217;expression des g\u00e8nes, un processus complexe par lequel l&#8217;information contenue dans l&#8217;ADN est copi\u00e9e dans l&#8217;ARN pour finalement donner naissance \u00e0 toutes les prot\u00e9ines et \u00e0 la plupart des mol\u00e9cules r\u00e9gulatrices de la cellule. Si l&#8217;on imagine l\u2019ADN comme un manuel technique dense, l&#8217;expression des g\u00e8nes est la m\u00e9thode par laquelle la cellule en extrait les informations utiles.&nbsp;<\/p>\n\n\n\n<p>Des chercheurs de l&#8217;Istituto Italiano di Tecnologia (IIT) de G\u00eanes et du Laboratoire europ\u00e9en de biologie mol\u00e9culaire (EMBL) de Grenoble ont d\u00e9voil\u00e9 comment ce processus peut \u00eatre modul\u00e9 \u00e0 l&#8217;aide de petites mol\u00e9cules. L&#8217;\u00e9tude pose les fondements de l\u2019identification future de potentiels m\u00e9dicaments agissant directement sur les mutations g\u00e9n\u00e9tiques ou les modifications qui alt\u00e8rent le processus d&#8217;expression des g\u00e8nes, ciblant ainsi l&#8217;apparition de tumeurs ou de maladies g\u00e9n\u00e9tiques.<\/p>\n\n\n\n<p>L&#8217;article de recherche, <a href=\"https:\/\/www.nature.com\/articles\/s41467-024-48697-0\">publi\u00e9 dans <em>Nature Communications<\/em><\/a>, a \u00e9t\u00e9 coordonn\u00e9 par Marco De Vivo, chercheur principal du Laboratoire de mod\u00e9lisation mol\u00e9culaire &amp; de d\u00e9couverte de m\u00e9dicaments et Directeur associ\u00e9 \u00e0 l&#8217;Informatique \u00e0 l&#8217;IIT de G\u00eanes, et par Marco Marcia, Directeur de recherche \u00e0 l&#8217;EMBL Grenoble.<\/p>\n\n\n\n<p>Les r\u00e9sultats ont \u00e9t\u00e9 obtenus en int\u00e9grant l&#8217;expertise de l&#8217;EMBL et du <a href=\"https:\/\/www.embl.org\/partnerships\/local\/structural-biology\/\">Partenariat pour la biologie structurale<\/a> (PSB) en biochimie, biophysique et biologie structurelle, et en utilisant la ligne de faisceau automatis\u00e9e MASSIF-1 exploit\u00e9e conjointement par l&#8217;EMBL et l&#8217;<a href=\"https:\/\/www.esrf.fr\/home.html\">European Radiation Synchrotron Facility<\/a> (ESRF) pour fournir des photographies aux rayons X du processus. Ces travaux ont \u00e9t\u00e9 combin\u00e9s \u00e0 l&#8217;expertise de l&#8217;IIT en mati\u00e8re de simulation informatique, ce qui a permis d&#8217;\u00e9tudier les interactions physico-chimiques des mol\u00e9cules impliqu\u00e9es.<\/p>\n\n\n\n<p>L&#8217;\u00e9tude s&#8217;est concentr\u00e9e sur l&#8217;\u00e9pissage, l&#8217;un des principaux niveaux de contr\u00f4le du processus d&#8217;expression g\u00e9n\u00e9tique. L&#8217;\u00e9pissage, comme son nom l&#8217;indique, est un processus par lequel les machines mol\u00e9culaires de la cellule \u2018coupent et collent\u2019 des s\u00e9quences sp\u00e9cifiques d&#8217;ARN pour cr\u00e9er des versions fonctionnelles. Ces versions \u2018matures\u2019 de l&#8217;ARN remplissent ensuite diverses fonctions dans la cellule, notamment en servant d&#8217;instructions pour la production de prot\u00e9ines, ou directement en tant que r\u00e9gulateurs de divers processus cellulaires.<\/p>\n\n\n\n<p>&#8220;L&#8217;\u00e9tude du processus d&#8217;\u00e9pissage de l&#8217;ARN est tr\u00e8s complexe en raison des r\u00e9actions chimiques et des acteurs mol\u00e9culaires impliqu\u00e9s, tels que l&#8217;ARN, les prot\u00e9ines, les ions et les mol\u00e9cules d&#8217;eau. Gr\u00e2ce aux techniques modernes de simulation mol\u00e9culaire, nous avons acquis une compr\u00e9hension d\u00e9taill\u00e9e de ce qui se passe et de la mani\u00e8re d&#8217;intervenir pour moduler l&#8217;\u00e9pissage. Notre \u00e9tude nous a d\u00e9j\u00e0 permis de synth\u00e9tiser de nouvelles mol\u00e9cules semblables \u00e0 des m\u00e9dicaments, capables de moduler l&#8217;\u00e9pissage d&#8217;une mani\u00e8re nouvelle, sp\u00e9cifique et tr\u00e8s efficace,&#8221; commente Marco De Vivo.<\/p>\n\n\n\n<p>En effet, les chercheurs de l&#8217;IIT et de l&#8217;EMBL, avec le soutien d&#8217;EMBLEM, la branche de l&#8217;EMBL charg\u00e9e du transfert de technologies et de connaissances, et du bureau des brevets de l&#8217;IIT, ont r\u00e9cemment d\u00e9pos\u00e9 un brevet d\u00e9crivant de nouveaux compos\u00e9s chimiques agissant comme modulateurs de l&#8217;\u00e9pissage. \u00c0 l&#8217;avenir, en am\u00e9liorant encore ces compos\u00e9s, il pourrait \u00eatre possible de r\u00e9guler la production de prot\u00e9ines sp\u00e9cifiques li\u00e9es \u00e0 des g\u00e8nes d\u00e9fectueux ou \u00e0 des mutations g\u00e9n\u00e9tiques.<\/p>\n\n\n\n<p>&#8220;La visualisation de la modulation de l&#8217;\u00e9pissage au niveau quasi atomique est \u00e9poustouflante. Elle nous permet de contr\u00f4ler l&#8217;une des r\u00e9actions les plus fondamentales de la vie. \u00c0 plus long terme, nous allons consolider l&#8217;int\u00e9gration concluante de nos \u00e9tudes exp\u00e9rimentales biologiques avec les \u00e9tudes chimiques et computationnelles de nos collaborateurs, en visant un objectif ambitieux : d\u00e9velopper de nouveaux m\u00e9dicaments, tels que des antibact\u00e9riens et des agents antitumoraux,\u201d d\u00e9clare Marco Marcia.<\/p>\n\n\n\n<p>Cette recherche s&#8217;inscrit \u00e9galement dans le cadre de l&#8217;initiative RNA Flagship de l&#8217;IIT, consacr\u00e9e au d\u00e9veloppement et \u00e0 l&#8217;application de nouvelles technologies bas\u00e9es sur l&#8217;ARN.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>A new research paper published in Nature Communications lays the groundwork for the development of new drugs specific to genetic mutations or alterations responsible for the onset of tumours or genetic diseases.<\/p>\n","protected":false},"author":120,"featured_media":68731,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[17591],"tags":[312,303,183,37,547,70,3628,35,238],"embl_taxonomy":[9792,19331,5148],"class_list":["post-68727","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-science-technology","tag-drug-discovery","tag-emblem","tag-gene-expression","tag-grenoble","tag-marcia","tag-rna","tag-splicing","tag-structural-biology","tag-technology-transfer","embl_taxonomy-embl-grenoble","embl_taxonomy-marcia-group-visiting","embl_taxonomy-structural-biology-embl-grenoble"],"acf":{"featured":true,"show_featured_image":false,"field_target_display":"embl","field_article_language":{"value":"english","label":"English"},"article_intro":"<p>A new research paper published in <em>Nature Communications<\/em> lays the groundwork for the development of new drugs specific to genetic mutations or alterations responsible for the onset of tumours or genetic diseases<\/p>\n","related_links":false,"source_article":[{"publication_title":"Targeting the conserved active site of splicing machines with specific and selective small molecule modulators","publication_link":{"title":"","url":"https:\/\/www.nature.com\/articles\/s41467-024-48697-0","target":"_blank"},"publication_authors":"Silvestri I., et al.","publication_source":"Nature Communications","publication_date":"19 June 2024","publication_doi":"10.1038\/s41467-024-48697-0"}],"in_this_article":false,"press_contact":"EMBL Generic","article_translations":[{"translation_language":"Italiano","translation_anchor":"#Italian"},{"translation_language":"Fran\u00e7ais","translation_anchor":"#French"}],"languages":""},"embl_taxonomy_terms":[{"uuid":"a:3:{i:0;s:36:\"b14d3f13-5670-44fb-8970-e54dfd9c921a\";i:1;s:36:\"89e00fee-87f4-482e-a801-4c3548bb6a58\";i:2;s:36:\"8f81131e-d37c-470c-848f-618fce652295\";}","parents":[],"name":["EMBL Grenoble"],"slug":"embl-grenoble","description":"Where &gt; 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