{"id":70415,"date":"2024-09-18T11:28:20","date_gmt":"2024-09-18T09:28:20","guid":{"rendered":"https:\/\/www.embl.org\/news\/?p=70415"},"modified":"2024-09-23T18:24:10","modified_gmt":"2024-09-23T16:24:10","slug":"silencing-in-action-how-cells-repress-genomic-remnants-of-ancient-viruses","status":"publish","type":"post","link":"https:\/\/www.embl.org\/news\/science-technology\/silencing-in-action-how-cells-repress-genomic-remnants-of-ancient-viruses\/","title":{"rendered":"Silencing in action: how cells &#8216;repress&#8217; genomic remnants of ancient viruses"},"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 \t<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">It is crucial for organisms to be able to control which genes are expressed in which cells and when.\u00a0<\/span><\/li>\r\n \t<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Naturally occurring chemical modifications of DNA-binding histone proteins are believed to play an important role in this process; however, it had been unclear whether they play a causal role in instructing gene expression.\u00a0<\/span><\/li>\r\n \t<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Researchers from EMBL Heidelberg and their collaborators in EMBL Australia have experimentally shown that certain histone sites act as critical control sites that help prevent the spurious activation of parts of the genome, including sequences derived from ancient remnants of viruses.\u00a0<\/span><\/li>\r\n<\/ul><\/p>\n      <\/div>\n<\/article>\n\n\n\n\n<p>For any organism to survive and thrive, its cells must strictly control which genes are active when and where. New research from EMBL Heidelberg&#8217;s Noh Group and their collaborators from EMBL Australia sheds light on some of the key control sites that regulate this process, especially with respect to the activity of ancient viral sequences in the genome.&nbsp;<\/p>\n\n\n\n<p>Our genomes are huge \u2013 a typical human cell contains DNA with over 6 billion units of information (measured in &#8216;base pairs&#8217;). However, this treasure trove of information poses a challenge when it comes to looking up the right information at the right time to perform a specific function. This is where epigenetic signatures come into play.&nbsp;<\/p>\n\n\n\n<p>If you imagine the genome as a book, epigenetic marks are the highlights on its pages and the notes in its margins. Now, it is not always easy to know whether these marks are &#8216;instructive&#8217; \u2013 i.e. do they tell the cell &#8220;Here, read this&#8221; or &#8220;Don&#8217;t read this&#8221;? Or are they simply marks left behind by a previous reader, indicating that that portion of the book was visited before?<\/p>\n\n\n\n<p>It was this question that interested Kyung-Min Noh, Group Leader at EMBL Heidelberg, and her team. The researchers decided to focus on a molecule called H3.3, which belongs to a class of proteins called histones. Histones tightly bind to DNA in cells and help form its functional structure.&nbsp;<\/p>\n\n\n\n<p>The H3.3 protein has a couple of spots on its tail (called K9 and K27) that are frequently chemically modified. It is hypothesised that these modifications are epigenetic marks to help the cell make gene expression decisions. However, until now, it had never been experimentally proven that these are true control sites that instruct gene expression.<\/p>\n\n\n\n<p>The researchers decided to experimentally mutate these sites, thus creating a version of H3.3 that could not be chemically modified at these spots. Considering the book analogy above, this created a protected page that could not be highlighted or marked, allowing the scientists to directly explore the consequences of losing such marks.&nbsp;<\/p>\n\n\n\n<p>Moreover, this system allowed the researchers to vary <em>which<\/em> page was protected, allowing them to draw comparisons between the loss of modifications at one or the other control site.&nbsp;<\/p>\n\n\n\n<p>The scientists found that the mutation of these sites in mouse stem cells not only resulted in defects in cell differentiation, growth, and survival, it also caused spurious activation of genes across the genome. This included genes that should <em>not <\/em>be expressed in stem cells, such as immune system-specific genes.&nbsp;<\/p>\n\n\n\n<p>This suggested that a normal function of these sites is to maintain those genes in an inactivated \u2013 or &#8216;repressed&#8217; \u2013 state, allowing stem cells to remain stem cells. These effects were also different for the two control sites studied, showing that each of them plays a distinct role in gene regulation.&nbsp;<\/p>\n\n\n\n<p>Upon further analysis, the researchers found that some of these regions, which are typically repressed but were activated upon mutating the histone sites, are ancient remnants of viruses that have integrated into our genomes.&nbsp;<\/p>\n\n\n\n<p>&#8220;These regions are also called endogenous retroviruses (ERVs),&#8221; explained Matteo Trovato,  the study&#8217;s first author, a former PhD student in the Noh group, and currently a postdoc at IFOM, Italy. &#8220;Throughout evolution, they have been co-opted by the host\u2019s genome to exert regulatory functions. In immune cells, for example, 30% of the enhancers (a specific type of regulatory DNA element) are derived from ERVs.&#8221;<\/p>\n\n\n\n<p>The researchers found that by modifying the K9 site in stem cells, many such &#8216;cryptic&#8217; enhancers \u2013 regulatory DNA regions that are normally silenced \u2013 became active.&nbsp;<\/p>\n\n\n\n<p>&#8220;Repression of these unique genomic regions is crucial for preserving the cell\u2019s gene expression program balance,&#8221; said Noh. &#8220;Activation of the cryptic enhancers triggers a widespread rewiring of the gene regulatory network, ultimately impacting stem cell identity and functionality.&#8221;<\/p>\n\n\n\n<p>The study was carried out in collaboration with Chen Davidovich&#8217;s group at EMBL Australia, Benjamin Garcia\u2019s lab at Washington University in St. Louis, and Judith Zaugg&#8217;s team at EMBL Heidelberg. The results were recently <a href=\"https:\/\/www.nature.com\/articles\/s41467-024-51785-w\">published in the journal <em>Nature Communications<\/em><\/a><em>.&nbsp;<\/em><\/p>\n\n\n\n<p>&#8220;This is one of the first few studies conducted in a mammalian system showing that these histone residues play a causal role in gene regulation,&#8221; said Noh. &#8220;Understanding this process could have broader implications for developmental biology and disease research, particularly in cancer and neurological disorders, where gene regulation plays an essential role.&#8221;<\/p>\n\n\n\n<hr class=\"vf-divider\"\/>\n\n\n\n<h1 class=\"wp-block-heading\" id=\"Italiano\"><strong>Silenziamento in azione: come le cellule \u201creprimono\u201d i resti genomici di antichi virus<\/strong><\/h1>\n\n\n\n<h2 class=\"wp-block-heading\">Un gruppo di ricercatori dell\u2019EMBL ha identificato siti di controllo cellulare che regolano l&#8217;espressione genica e impediscono l&#8217;attivazione di regioni genomiche \u201ccriptiche\u201d, tra cui antiche sequenze virali.<\/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 \t<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Per tutti gli organismi viventi \u00e8 fondamentale poter controllare quali geni vengono espressi in quali cellule e in quale momento.  \u00a0<\/span><\/li>\r\n \t<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Si ritiene che le modifiche chimiche naturali degli istoni (proteine che legano il DNA) svolgano un ruolo importante in questo processo; tuttavia, finora non era chiaro se svolgessero un ruolo causale nel regolare l&#8217;espressione dei geni.  <\/span><\/li>\r\n \t<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">I ricercatori dell&#8217;EMBL di Heidelberg e i loro collaboratori dell&#8217;EMBL Australia hanno dimostrato sperimentalmente che alcuni residui istonici agiscono come siti di controllo critici che prevengono l&#8217;attivazione impropria di alcune parti del genoma, comprese sequenze derivanti da antichi resti di virus.  \u00a0<\/span><\/li>\r\n \t<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">La comprensione di questo processo potrebbe avere implicazioni significative per la biologia dello sviluppo e per la ricerca sulle malattie, in particolare nel cancro e nei disturbi neurologici, dove una regolazione genica adeguata \u00e8 cruciale.<\/span><\/li>\r\n<\/ul><\/p>\n      <\/div>\n<\/article>\n\n\n\n\n<p>Affinch\u00e9 un organismo possa sopravvivere e prosperare, le sue cellule devono controllare rigorosamente quali geni sono attivi quando e dove. Una nuova ricerca del gruppo Noh dell&#8217;EMBL di Heidelberg e dei suoi collaboratori dell&#8217;EMBL Australia fa luce su alcuni dei siti di controllo chiave che regolano questo processo, soprattutto per quanto riguarda l&#8217;attivit\u00e0 di antiche sequenze virali presenti nel genoma.<\/p>\n\n\n\n<p>I nostri genomi sono enormi: una tipica cellula umana contiene oltre 6 miliardi di unit\u00e0 di informazioni sul DNA (misurate in \u201ccoppie di basi\u201d). Tuttavia, questa enorme quantit\u00e0 di informazioni rappresenta una sfida quando si tratta di cercare quelle giuste, al momento giusto, per svolgere una funzione specifica. \u00c8 qui che entrano in gioco le modifiche epigenetiche.<\/p>\n\n\n\n<p>Se immaginiamo il genoma come un libro, le modifiche epigenetiche rappresentano le sottolineature e le note a margine. Non \u00e8 per\u00f2 sempre facile capire se questi segni siano \u201cistruttivi\u201d, cio\u00e8 se indichino alla cellula cosa \u201cleggere\u201d, o se siano semplicemente tracce lasciate da un lettore precedente, che indicano che quella parte del libro \u00e8 stata gi\u00e0 esplorata.<\/p>\n\n\n\n<p>\u00c8 questa la domanda che ha interessato il ricercatore italiano Matteo Trovato e Kyung-Min Noh, Group Leader dell&#8217;EMBL di Heidelberg. I ricercatori hanno deciso di concentrarsi su una molecola chiamata H3.3, che appartiene a una classe di proteine chiamate istoni. Gli istoni si legano strettamente al DNA nelle cellule e contribuiscono a formarne la struttura funzionale.<\/p>\n\n\n\n<p>La proteina H3.3 presenta due siti sulla sua coda, chiamati K9 e K27, che vengono spesso modificati chimicamente. Sebbene si ritenga che queste modifiche epigenetiche contribuiscano al controllo &nbsp;dell&#8217;espressione genica, finora non era mai stato dimostrato sperimentalmente che questi siti funzionassero effettivamente come strumenti di regolazione.<\/p>\n\n\n\n<p>I ricercatori hanno deciso di mutare sperimentalmente questi siti, creando cos\u00ec una versione di H3.3 che non poteva essere modificata chimicamente in quei punti. Riprendendo l&#8217;analogia del libro, \u00e8 come se avessero creato una \u201cpagina protetta\u201d, impossibile da evidenziare o contrassegnare. Questo ha permesso agli scienziati di esplorare direttamente le conseguenze della mancanza di tali \u201cannotazioni\u201d epigenetiche e capire meglio il loro ruolo nella regolazione dell\u2019espressione genica.<\/p>\n\n\n\n<p>Inoltre, questo sistema ha permesso ai ricercatori di variare la pagina protetta, consentendo loro di confrontare gli effetti della perdita di modifiche in uno o nell&#8217;altro sito di controllo.<\/p>\n\n\n\n<p>Gli scienziati hanno scoperto che la mutazione di questi siti nelle cellule staminali di topo non solo provoca difetti nella differenziazione, nella crescita e nella sopravvivenza delle cellule, ma porta anche all&#8217;attivazione impropria di geni in tutto il genoma. Tra questi vi sono geni che normalmente non dovrebbero essere attivati nelle cellule staminali, come quelli specifici del sistema immunitario.<\/p>\n\n\n\n<p>Questo risultato suggerisce che una funzione normale di questi siti di controllo \u00e8 quella di mantenere molti geni in uno stato inattivo, o \u201crepresso\u201d, permettendo alle cellule staminali di conservare la loro identit\u00e0. Gli effetti delle mutazioni sui due siti di controllo studiati si sono rivelati diversi, dimostrando che ciascuno di essi svolge un ruolo specifico e distinto nella regolazione genica.<\/p>\n\n\n\n<p>Dopo ulteriori analisi, i ricercatori hanno scoperto che alcune di queste regioni, tipicamente represse ma attivate a causa delle mutazioni dei siti istonici, sono antichi resti di virus che si sono integrati nei nostri genomi.<\/p>\n\n\n\n<p>\u201cQueste regioni sono chiamate anche elementi retrovirali endogeni (ERV)\u201d, ha spiegato Matteo Trovato, ex dottorando del gruppo di Noh e primo autore dello studio, attualmente postdoc presso l&#8217;IFOM di Milano. \u201cNel corso dell&#8217;evoluzione, questi elementi virali sono stati cooptati dal genoma dell&#8217;ospite per svolgere funzioni regolatorie. Ad esempio, nelle cellule immunitarie, circa il 30% degli enhancer (un tipo specifico di elemento regolatore del DNA) deriva dagli ERV\u201d.<\/p>\n\n\n\n<p>I ricercatori hanno scoperto che modificando il sito K9 nelle cellule staminali, molti di questi enhancer \u201ccriptici\u201d &#8211; regioni di DNA regolatore normalmente silenziate &#8211; diventano attivi.<\/p>\n\n\n\n<p>\u201cLa repressione di queste regioni genomiche uniche \u00e8 fondamentale per preservare l&#8217;equilibrio del programma di espressione genica della cellula\u201d, ha detto Noh. \u201cL&#8217;attivazione degli enhancer criptici innesca un&#8217;ampia ricablatura della rete di regolazione genica, con un impatto finale sull&#8217;identit\u00e0 e la funzionalit\u00e0 delle cellule staminali\u201d.<\/p>\n\n\n\n<p>Lo studio \u00e8 stato condotto in collaborazione con il gruppo di Chen Davidovich dell&#8217;EMBL Australia, il laboratorio di Benjamin Garcia della Washington University di St. Louis e il team di Judith Zaugg dell&#8217;EMBL di Heidelberg. I risultati sono stati recentemente <a href=\"https:\/\/www.nature.com\/articles\/s41467-024-51785-w\">pubblicati sulla rivista Nature Communications<\/a>.<\/p>\n\n\n\n<p>\u201cQuesto \u00e8 uno dei primi studi condotti in cellule di mammifero che dimostra come questi residui istonici svolgano un ruolo causale nella regolazione genica\u201d, ha detto Noh. \u201cComprendere questo processo potrebbe avere implicazioni pi\u00f9 ampie per la biologia dello sviluppo e la ricerca sulle malattie, in particolare nel cancro e nei disturbi neurologici, dove una corretta regolazione genica \u00e8 cruciale\u201d.<\/p>\n\n\n\n\n","protected":false},"excerpt":{"rendered":"<p>Researchers have identified key cellular control sites that regulate gene expression and prevent the activation of ancient viral sequences in the genome.<\/p>\n","protected":false},"author":124,"featured_media":70417,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[17591],"tags":[39,43,2016,954,741,17249,13989],"embl_taxonomy":[9796,19345],"class_list":["post-70415","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-science-technology","tag-epigenetics","tag-heidelberg","tag-histone","tag-mouse","tag-noh","tag-nucleosome","tag-stem-cells","embl_taxonomy-embl-heidelberg","embl_taxonomy-noh-group-visiting"],"acf":{"vf_locked":false,"featured":true,"show_featured_image":false,"field_target_display":"embl","field_article_language":{"value":"english","label":"English"},"article_intro":"<p>Researchers have identified key cellular control sites that regulate gene expression and prevent the activation of &#8216;cryptic&#8217; genomic regions, including ancient viral sequences<\/p>\n","related_links":[{"link_description":"Genome Biology Unit\r\n","link_url":"https:\/\/www.embl.org\/research\/units\/genome-biology\/"},{"link_description":"Noh Group","link_url":"https:\/\/www.embl.org\/groups\/noh\/"}],"source_article":[{"publication_title":"Histone H3.3 lysine 9 and 27 control repressive chromatin at cryptic enhancers and bivalent promoters.","publication_link":{"title":"","url":"https:\/\/www.nature.com\/articles\/s41467-024-51785-w","target":""},"publication_authors":"Trovato M., et al.","publication_source":"Nature Communications","publication_date":"30 August 2024","publication_doi":"10.1038\/s41467-024-51785-w"}],"in_this_article":false,"press_contact":"EMBL Generic","article_translations":[{"translation_language":"Italiano","translation_anchor":"#Italiano"}],"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:\"ab46b6d4-71d8-49f8-b2f4-b326d4c8ea4e\";}","parents":[],"name":["EMBL Heidelberg"],"slug":"embl-heidelberg","description":"Where &gt; All EMBL sites &gt; EMBL Heidelberg"},{"uuid":"a:3:{i:0;s:36:\"302cfdf7-365b-462a-be65-82c7b783ebf7\";i:1;s:36:\"fe59a59f-fd7d-49b3-b3e4-bdd33a6642c3\";i:2;s:36:\"eb3946ec-c9ad-4ae3-a2e0-8e83fd0e0587\";}","parents":[],"name":["Noh Group (Visiting)"],"slug":"noh-group-visiting","description":"What &gt; Genome Biology &gt; Noh Group (Visiting)"}],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.2 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>Silencing in action: how cells &#039;repress&#039; genomic remnants of ancient viruses | EMBL<\/title>\n<meta name=\"description\" content=\"Researchers have identified key cellular control sites that prevent the activation of ancient viral sequences in the genome\" \/>\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\/silencing-in-action-how-cells-repress-genomic-remnants-of-ancient-viruses\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Silencing in action: how cells &#039;repress&#039; 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