{"id":67995,"date":"2024-05-09T11:10:28","date_gmt":"2024-05-09T09:10:28","guid":{"rendered":"https:\/\/www.embl.org\/news\/?p=67995"},"modified":"2024-05-09T11:10:34","modified_gmt":"2024-05-09T09:10:34","slug":"an-epigenome-editing-toolkit-to-dissect-the-mechanisms-of-gene-regulation","status":"publish","type":"post","link":"https:\/\/www.embl.org\/news\/science-technology\/an-epigenome-editing-toolkit-to-dissect-the-mechanisms-of-gene-regulation\/","title":{"rendered":"An epigenome editing toolkit to dissect the mechanisms of gene regulation"},"content":{"rendered":"\n<p>Understanding how genes are regulated at the molecular level is a central challenge in modern biology. This complex mechanism is mainly driven by the interaction between proteins called transcription factors, DNA regulatory regions, and epigenetic modifications \u2013 chemical alterations that change chromatin structure. The set of epigenetic modifications of a cell\u2019s genome is referred to as the epigenome.<\/p>\n\n\n\n<p>In a study just published in <em>Nature Genetics<\/em>, scientists from the Hackett Group at EMBL Rome have developed a modular epigenome editing platform \u2013 a system to program epigenetic modifications at any location in the genome. The system allows scientists to study the impact of each chromatin modification on transcription, the mechanism by which genes are copied into mRNA to drive protein synthesis.&nbsp;<\/p>\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      What is chromatin?    <\/h3>\n                <p class=\"vf-card__text\"><span style=\"font-weight: 400;\">Inside the cell\u2019s nucleus, DNA is wrapped around positively charged proteins called histones that strongly adhere to the negatively charged DNA. The individual units of DNA with accompanying histones are called nucleosomes, which assemble in a highly ordered structure, called chromatin. <\/span>\r\n\r\n<span style=\"font-weight: 400;\">Chromatin structure is known to play a major role in gene regulation, since it influences the accessibility of DNA regulatory regions to transcription factors, proteins that help turn gene expression on or off. However, the extent to which chemical modifications of DNA and histones, collectively referred to as \u2018chromatin marks\u2019, contribute to transcription regulation has so far remained unclear.<\/span><\/p>\n      <\/div>\n<\/article>\n\n\n\n\n<p>Chromatin modifications are thought to contribute to the regulation of key biological processes such as development, response to environmental signals, and disease.<\/p>\n\n\n\n<p>To understand the effects of specific chromatin marks on gene regulation, previous studies have mapped their distribution in the genomes of healthy and diseased cell types. By combining this data with gene expression analysis and the known effects of perturbing specific genes, scientists have ascribed functions to such chromatin marks.&nbsp;<\/p>\n\n\n\n<p>However, the causal relationship between chromatin marks and gene regulation has proved difficult to determine. The challenge lies in dissecting the individual contributions of the many complex factors involved in such regulation \u2013 chromatin marks, transcription factors, and regulatory DNA sequences.<\/p>\n\n\n\n<p>Scientists from the Hackett Group developed a modular epigenome editing system to precisely program nine biologically important chromatin marks at any desired region in the genome. The system is based on CRISPR \u2013 a widely used genome editing technology that allows researchers to make alterations in specific DNA locations with high precision and accuracy.&nbsp;<\/p>\n\n\n\n<p>Such precise perturbations enabled&nbsp; them to carefully dissect cause-and-consequence relationships between chromatin marks and their biological effects.&nbsp; The scientists also designed and employed a \u2018reporter system\u2019, which allowed them to measure changes in gene expression at single-cell level and to understand how changes in the DNA sequence influence the impact of each chromatin mark. Their results reveal the causal roles of a range of important chromatin marks in&nbsp; gene regulation.<\/p>\n\n\n\n<figure class=\"vf-figure wp-block-image  | vf-figure--align vf-figure--align-inline-start   size-large is-resized\"><img loading=\"lazy\" decoding=\"async\" width=\"765\" height=\"1024\" class=\"vf-figure__image\" src=\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2024\/05\/Policarpi_NatGen_cover_final_small-765x1024.jpg\" alt=\"\" class=\"wp-image-68009\" style=\"width:381px;height:auto\" srcset=\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2024\/05\/Policarpi_NatGen_cover_final_small-765x1024.jpg 765w, https:\/\/www.embl.org\/news\/wp-content\/uploads\/2024\/05\/Policarpi_NatGen_cover_final_small-224x300.jpg 224w, https:\/\/www.embl.org\/news\/wp-content\/uploads\/2024\/05\/Policarpi_NatGen_cover_final_small-768x1027.jpg 768w, https:\/\/www.embl.org\/news\/wp-content\/uploads\/2024\/05\/Policarpi_NatGen_cover_final_small.jpg 1510w\" sizes=\"auto, (max-width: 765px) 100vw, 765px\" \/><\/figure>\n\n\n\n<p>For example, the researchers&nbsp; found a new role for H3K4me3, a chromatin mark that was previously believed to be a result of transcription. They observed that H3K4me3 can actually increase transcription by itself if artificially added to specific DNA locations. \u201cThis was an extremely exciting and unexpected result that went against all our expectations,\u201d said Cristina Policarpi, postdoc in the Hackett Group and leading scientist of the study. \u201cOur data point towards a complex regulatory network, in which multiple governing factors interact to modulate the levels of gene expression in a given cell. These factors include the pre-existing structure of the chromatin, the underlying DNA sequence, and the location in the genome.\u201d&nbsp;<\/p>\n\n\n\n<p>Hackett and colleagues are currently exploring avenues to leverage this technology through a promising start-up venture. The next step will be to confirm and expand these conclusions by targeting genes across different cell types and at scale.&nbsp; How chromatin marks influence transcription across the diversity of genes and downstream mechanisms, also remains to be clarified.&nbsp;&nbsp;<\/p>\n\n\n\n<p>\u201cOur modular epigenetic editing toolkit constitutes a new experimental approach to dissect the reciprocal relationships between the genome and epigenome,\u201d said Jamie Hackett, Group Leader at EMBL Rome. \u201cThe system could be used in the future to more precisely understand the importance of epigenomic changes in influencing gene activity during development and in human disease. On the other hand, the technology also unlocks the ability to program desired gene expression levels in a highly tunable manner. This is an exciting avenue for precision health applications and may prove useful in disease settings.\u201d<\/p>\n\n\n\n<hr class=\"vf-divider\"\/>\n\n\n\n<h1 class=\"wp-block-heading\" id=\"a1\"><strong>Un sistema di editing epigenetico per analizzare il meccanismo di regolazione dei geni<\/strong><\/h1>\n\n\n\n<h2 class=\"wp-block-heading\">Uno studio del gruppo di Jamie Hackett dello European Molecular Biology Laboratory (EMBL) di Roma ha portato allo sviluppo di una potente tecnologia di editing epigenetico, che consente di programmare con precisione le modifiche della cromatina.<\/h2>\n\n\n\n<figure class=\"vf-figure wp-block-image size-full\"><img loading=\"lazy\" decoding=\"async\" width=\"1000\" height=\"600\" class=\"vf-figure__image\" src=\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2024\/05\/Cover-Image-1000x600-1.jpg\" alt=\"\" class=\"wp-image-67999\" srcset=\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2024\/05\/Cover-Image-1000x600-1.jpg 1000w, https:\/\/www.embl.org\/news\/wp-content\/uploads\/2024\/05\/Cover-Image-1000x600-1-300x180.jpg 300w, https:\/\/www.embl.org\/news\/wp-content\/uploads\/2024\/05\/Cover-Image-1000x600-1-768x461.jpg 768w\" sizes=\"auto, (max-width: 1000px) 100vw, 1000px\" \/><figcaption class=\"vf-figure__caption\">Detail of a creative depiction of the epigenetic editing toolkit: each building represents the epigenetic state of a single gene (dark windows are silenced genes, lit up windows are active genes). The crane illustrates the epigenetic editing system which enables de novo deposition of chromatin marks on any genomic location. Full image in the text. Credits: Marzia Munaf\u00f2 (munafomarzia.com)<\/figcaption><\/figure>\n\n\n\n<p>Comprendere la regolazione dei geni a livello molecolare \u00e8 una sfida centrale della biologia moderna. Questo complesso meccanismo \u00e8 guidato principalmente dall&#8217;interazione tra fattori di trascrizione, regioni regolatrici del DNA e modifiche epigenetiche &#8211; alterazioni chimiche che cambiano la struttura della cromatina.&nbsp;<\/p>\n\n\n\n<p>In uno studio appena pubblicato su <em>Nature Genetics<\/em>, gli scienziati del gruppo di Jamie Hackett all\u2019EMBL di Roma hanno sviluppato una piattaforma modulare per l&#8217;editing epigenetico &#8211; un sistema che permette di programmare modifiche epigenetiche in qualunque posizione del genoma. Questa tecnologia consente di studiare l&#8217;impatto di ciascuna modifica della cromatina sulla trascrizione &#8211; il meccanismo attraverso cui i geni vengono copiati in una molecola di mRNA per guidare la sintesi delle proteine.&nbsp;<\/p>\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      Cos&#039;\u00e8 la cromatina    <\/h3>\n                <p class=\"vf-card__text\"><span style=\"font-weight: 400;\">All&#8217;interno del nucleo della cellula, il DNA \u00e8 avvolto da proteine a carica positiva chiamate istoni che si legano al DNA che ha carica negativa. Le singole unit\u00e0 di DNA e istoni, chiamate nucleosomi, si assemblano in una struttura altamente ordinata &#8211; la cromatina.<\/span>\r\n\r\n<span style=\"font-weight: 400;\">\u00a0<\/span>\r\n\r\n<span style=\"font-weight: 400;\">\u00c8 noto che la struttura della cromatina svolge un ruolo importante nella regolazione dei geni, poich\u00e9 influenza l&#8217;accesso dei fattori di trascrizione (le proteine che accendono e spengono i geni) alle regioni regolatrici del DNA. Tuttavia non \u00e8 chiaro in che modo le modifiche chimiche sul DNA e sugli istoni contribuiscono alla regolazione della trascrizione.<\/span><\/p>\n      <\/div>\n<\/article>\n\n\n\n\n<p>Le modifiche della cromatina contribuiscono alla regolazione di processi biologici chiave come lo sviluppo, la risposta ai segnali ambientali e le malattie.<\/p>\n\n\n\n<p>Per comprendere l&#8217;effetto specifico di queste modifiche epigenetiche sulla regolazione dei geni, alcuni studi precedenti hanno mappato la loro distribuzione nel genoma di cellule sane e malate. Combinando questi dati con l\u2019analisi dell\u2019espressione genica gli scienziati hanno potuto solo dedurre la funzione di alcune modifiche della cromatina.&nbsp;<\/p>\n\n\n\n<p>Tuttavia, stabilire una relazione causale tra le modifiche della cromatina e la regolazione genica non \u00e8 semplice, poich\u00e9 \u00e8 necessario analizzare il contributo dei singoli fattori coinvolti nel processo &#8211; oltre alle modifiche della cromatina anche i fattori di trascrizione e le sequenze di DNA regolatrici.<\/p>\n\n\n\n<p>I ricercatori del gruppo di Hackett hanno sviluppato un sistema modulare di editing epigenetico che consente di programmare con precisione nove modifiche epigenetiche biologicamente importanti in qualsiasi regione del genoma. Il sistema \u00e8 basato su CRISPR, una tecnologia ampiamente utilizzata dai ricercatori per alterare regioni specifiche del DNA con elevata precisione e accuratezza.<\/p>\n\n\n\n<p>Questo sistema ha permesso di analizzare in maniera precisa le relazioni di causa-effetto tra le modifiche della cromatina e il loro effetto biologico. I ricercatori hanno inoltre utilizzato geni reporter&nbsp; per misurare i livelli di espressione genica in&nbsp; singole cellule e capire come i cambiamenti nella sequenza del DNA influenzano&nbsp; l\u2019effetto ultimo&nbsp; delle modifiche della cromatina sulla trascrizione. I risultati hanno rivelato il contributo specifico di alcune importanti modifiche epigenetiche nella regolazione genica.&nbsp;<\/p>\n\n\n\n<p><br \/>Ad esempio, i ricercatori hanno scoperto un nuovo ruolo di H3K4me3, una modifica della cromatina che generalmente si pensava fosse una conseguenza dell&#8217;attivit\u00e0 trascrizionale. I risultati dello studio hanno mostrato che invece H3K4me3 \u00e8 in grado di aumentare la trascrizione quando viene depositata in corrispondenza di alcuni geni.&nbsp;<\/p>\n\n\n\n<p>\u201cSi tratta di un risultato estremamente eccitante e inaspettato, che va contro tutte le nostre previsioni&#8221;, ha commentato Cristina Policarpi, postdoc del Gruppo Hackett e prima autrice dello studio. \u201cI nostri dati suggeriscono una complessa rete di regolazione, in cui molteplici fattori intervengono per modulare i livelli di espressione genica nella cellula. Questi fattori includono lo stato preesistente della cromatina, la sequenza del DNA e la posizione dei geni nel genoma.\u201d&nbsp;<\/p>\n\n\n\n<p>Il prossimo passo per il gruppo di Hackett sar\u00e0 confermare ed estendere queste conclusioni analizzando un gran numero di&nbsp; geni in diversi tipi di cellule e di organismi.&nbsp; Resta da chiarire il meccanismo attraverso cui le modifiche della cromatina influenzano la trascrizione e interagiscono&nbsp; con gli altri elementi regolatori.<\/p>\n\n\n\n<p>&#8220;Il nostro kit di editing epigenetico costituisce un nuovo approccio sperimentale per analizzare le relazioni reciproche tra genoma ed epigenoma&#8221;, ha dichiarato Jamie Hackett, Group Leader dell&#8217;EMBL di Roma. \u201cIl sistema potrebbe essere utilizzato per comprendere con maggiore precisione l&#8217;importanza dei cambiamenti epigenetici nell&#8217;influenzare l&#8217;attivit\u00e0 dei geni durante lo sviluppo e nelle malattie umane. D&#8217;altra parte, la tecnologia apre anche la possibilit\u00e0 di programmare e modulare con un\u2019elevata precisione i livelli di espressione genica desiderati. Si tratta di una strada entusiasmante per le applicazioni nella medicina di precisione e potrebbe rivelarsi utile in alcune patologie.&#8221;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>A study from the Hackett group at EMBL Rome led to the development of an epigenetic editing system that allows to precisely program chromatin modifications at any specific position in the genome, to understand their causal role in transcription regulation.<\/p>\n","protected":false},"author":92,"featured_media":67999,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[17591],"tags":[536,537,303,17251,39,778,40,41,664,13987,17665,514,238],"embl_taxonomy":[9788,5144,18953],"class_list":["post-67995","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-science-technology","tag-chromatin","tag-dna","tag-emblem","tag-epigenetic","tag-epigenetics","tag-gene","tag-gene-regulation","tag-genetics","tag-genome","tag-innovation","tag-invention","tag-rome","tag-technology-transfer","embl_taxonomy-embl-rome","embl_taxonomy-epigenetics-and-neurobiology","embl_taxonomy-james-hackett"],"acf":{"featured":true,"show_featured_image":false,"field_target_display":"embl","field_article_language":{"value":"english","label":"English"},"article_intro":"<p>A study from the Hackett group at EMBL Rome led to the development of a powerful epigenetic editing technology, which unlocks the ability to precisely program chromatin modifications<\/p>\n","related_links":[{"link_description":"Hackett group","link_url":"https:\/\/www.embl.org\/groups\/hackett\/"}],"source_article":[{"publication_title":"Systematic Epigenome Editing Captures the Context-dependent Instructive Function of Chromatin Modifications","publication_link":{"title":"","url":"https:\/\/www.nature.com\/articles\/s41588-024-01706-w","target":""},"publication_authors":"Policarpi C., et al., ","publication_source":"Nature Genetics","publication_date":"9 May 2024 ","publication_doi":"10.1038\/s41588-024-01706-w"}],"in_this_article":false,"press_contact":"EMBL Generic","article_translations":[{"translation_language":"Italiano","translation_anchor":"#a1"}],"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:\"741d5d3d-f92f-4eb8-9195-55c96454a36b\";}","parents":[],"name":["EMBL Rome"],"slug":"embl-rome","description":"Where &gt; All EMBL sites &gt; EMBL Rome"},{"uuid":"a:3:{i:0;s:36:\"302cfdf7-365b-462a-be65-82c7b783ebf7\";i:1;s:36:\"7ca3ce91-dc32-47ea-8d4b-7a53c3a3a9fd\";i:2;s:36:\"a6e35bb0-c32d-4c9b-aadb-a19b6c7b060f\";}","parents":[],"name":["Epigenetics and neurobiology"],"slug":"epigenetics-and-neurobiology","description":"What &gt; Research Units &gt; Epigenetics and neurobiology"},{"uuid":"a:2:{i:0;s:36:\"4428d1fd-441a-4d6d-a1c5-5dcf5665f213\";i:1;s:36:\"e87754e5-4651-419c-be09-c6168b4bd6dc\";}","parents":[],"name":["James Hackett"],"slug":"james-hackett","description":"Who &gt; James Hackett"}],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.2 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>An epigenome editing toolkit to dissect the mechanisms of gene regulation | EMBL<\/title>\n<meta name=\"description\" content=\"A study from the Hackett group at EMBL Rome led to the development of an epigenetic editing system to investigate the causal impact of chromatin modifications on gene regulation.\" \/>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.embl.org\/news\/science-technology\/an-epigenome-editing-toolkit-to-dissect-the-mechanisms-of-gene-regulation\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"An epigenome editing toolkit to dissect the mechanisms of gene regulation | EMBL\" \/>\n<meta property=\"og:description\" content=\"A study from the Hackett group at EMBL Rome led to the development of an epigenetic editing system to investigate the causal impact of chromatin modifications on gene regulation.\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.embl.org\/news\/science-technology\/an-epigenome-editing-toolkit-to-dissect-the-mechanisms-of-gene-regulation\/\" \/>\n<meta property=\"og:site_name\" content=\"EMBL\" \/>\n<meta property=\"article:publisher\" content=\"https:\/\/www.facebook.com\/embl.org\/\" \/>\n<meta property=\"article:published_time\" content=\"2024-05-09T09:10:28+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2024-05-09T09:10:34+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2024\/05\/Cover-Image-1000x600-1.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"1000\" \/>\n\t<meta property=\"og:image:height\" content=\"600\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"Rossana De Lorenzi\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:creator\" content=\"@embl\" \/>\n<meta name=\"twitter:site\" content=\"@embl\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Rossana De Lorenzi\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"7 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"NewsArticle\",\"@id\":\"https:\/\/www.embl.org\/news\/science-technology\/an-epigenome-editing-toolkit-to-dissect-the-mechanisms-of-gene-regulation\/#article\",\"isPartOf\":{\"@id\":\"https:\/\/www.embl.org\/news\/science-technology\/an-epigenome-editing-toolkit-to-dissect-the-mechanisms-of-gene-regulation\/\"},\"author\":{\"name\":\"Rossana De Lorenzi\",\"@id\":\"https:\/\/www.embl.org\/news\/#\/schema\/person\/09fbcca4054ca2db027d0e970b2f1296\"},\"headline\":\"An epigenome editing toolkit to dissect the mechanisms of gene regulation\",\"datePublished\":\"2024-05-09T09:10:28+00:00\",\"dateModified\":\"2024-05-09T09:10:34+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\/\/www.embl.org\/news\/science-technology\/an-epigenome-editing-toolkit-to-dissect-the-mechanisms-of-gene-regulation\/\"},\"wordCount\":1394,\"publisher\":{\"@id\":\"https:\/\/www.embl.org\/news\/#organization\"},\"image\":{\"@id\":\"https:\/\/www.embl.org\/news\/science-technology\/an-epigenome-editing-toolkit-to-dissect-the-mechanisms-of-gene-regulation\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2024\/05\/Cover-Image-1000x600-1.jpg\",\"keywords\":[\"chromatin\",\"dna\",\"emblem\",\"epigenetic\",\"epigenetics\",\"gene\",\"gene regulation\",\"genetics\",\"genome\",\"innovation\",\"invention\",\"rome\",\"technology transfer\"],\"articleSection\":[\"Science &amp; 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