{"id":16816,"date":"2019-09-15T07:30:32","date_gmt":"2019-09-15T07:30:32","guid":{"rendered":"https:\/\/www.revoscience.com\/en\/?p=16816"},"modified":"2020-06-09T12:41:35","modified_gmt":"2020-06-09T12:41:35","slug":"new-cardiac-fibrosis-study-identifies-key-proteins-that-translate-into-heart-disease","status":"publish","type":"post","link":"https:\/\/www.revoscience.com\/en\/new-cardiac-fibrosis-study-identifies-key-proteins-that-translate-into-heart-disease\/","title":{"rendered":"New cardiac fibrosis study identifies key proteins that translate into heart disease"},"content":{"rendered":"\n

The formation of excess fibrous tissue in the heart, which underlies several heart diseases, could be prevented by inhibiting specific proteins that bind to RNA while its code is being translated.<\/em><\/strong><\/p>\n\n\n\n

\"\"<\/figure>\n\n\n\n

Using\ncutting-edge technologies, researchers at Duke-NUS Medical School, Singapore,\nhave developed the first genome-wide dataset on protein translation during\nfibroblast activation, revealing a network of RNA-binding proteins (RBPs) that\nplay a key role in the formation of disease-causing fibrous tissue in the\nheart. Their findings, published in the journal Circulation, could help in the\nsearch for treatments for this condition.<\/p>\n\n\n\n

Cardiac\nfibrosis, a condition characterised by scarring in the heart, is caused by the\nactivation of fibre-producing cells called fibroblasts \u2013 which form one of the\nlargest groups of cells in the heart \u2013 and underlies many heart diseases,\nincluding atrial fibrillation, dilated cardiomyopathy, and heart failure. This\ninvolves the transformation of fibroblasts into myofibroblasts, which leads to\nthickening and stiffening of the heart wall, making it less contractile and\nthus less able to pump blood around the body.<\/p>\n\n\n\n

\u201cHeart\ndisease is a prominent cause of mortality, accounting for one in three deaths\nin Singapore. In most cases, they are preceded by the transition of resident\nfibroblasts to myofibroblasts,\u201d explained computational geneticist Dr Owen\nRackham, corresponding author of the study and Assistant Professor in the\nCardiovascular and Metabolic Disorders (CVMD) Programme at Duke-NUS. \u201cDespite\nthe serious risk and high prevalence of cardiac fibrosis, existing therapies\nare ineffective and there is an unmet need for new therapeutic approaches to\nprevent, limit, or reverse the condition.\u201d<\/p>\n\n\n\n

Being able\nto disentangle the processes underlying the transformation of fibroblasts into\nmyofibroblasts could help unveil novel molecular pathways underpinning disease\nonset and pathophysiology, and aid in the search for novel therapeutic targets.\nThe team of researchers from Duke-NUS and colleagues in Germany and the UK\ninvestigated the processes that regulate the transcription of DNA code into\nRNA, and the translation of that code from RNA for protein synthesis during the\ntransformation of fibroblasts into myofibroblasts.<\/p>\n\n\n\n

\u201cWe found a\nstaggering one-third of all genes undergo translational regulation during this\npathogenic transition,\u201d highlighted Ms Sonia Chothani, first author of the\nstudy and a PhD student at Duke-NUS. \u201cAll these gene expression changes are\nmissed or misinterpreted in traditional RNA-based studies.\u201d<\/p>\n\n\n\n

The team\nfirst analysed the gene changes that occurred during DNA transcription and RNA\ntranslation at different time points in the fibroblast-to-myofibroblast\ntransition. A computational analysis of this data identified specific\nregulatory processes affecting RNA translation. They then analysed RNA found in\nfibroblasts from tissue samples taken from patients with dilated\ncardiomyopathy. Many of the regulatory processes identified in the\ncomputational analysis were active in the diseased tissue samples.<\/p>\n\n\n\n

Specifically,\nthe researchers found RBPs play critical roles in the\nfibroblast-to-myofibroblast transformation. RBPs target RNA, affecting the\ntranslation of its code during protein synthesis. Inhibiting two of these RBPs,\ncalled PUM2 and QKI, limited the transformation of fibroblasts into\nmyofibroblasts.<\/p>\n\n\n\n

\u201cThere are\nmore than 1,500 RBPs encoded in the human genome, but their role in the\nregulation of translation of target messenger RNAs remains largely unexplored.\nOur findings show the central importance of translational control in fibrosis,\nand highlight novel pathogenic mechanisms in heart failure,\u201d said Dr Rackham.\n\u201cJust as transcription factors are emerging targets in pharmacology owing to\ntheir centrality in the dysregulation of transcription, we show that RBPs may\nplay a similar role in the dysregulation of translation.\u201d<\/p>\n\n\n\n

\u201cOur study\ncombines the use of primary cardiac fibroblasts and heart tissue samples with\ncutting-edge technologies, leading to the first genome-wide dataset on protein\ntranslation during fibroblast activation, which we were also able to follow-up\nin the diseased human heart,\u201d said Dr Stuart Cook, a senior co-author of the\nstudy, the Tanoto Foundation Professor of Cardiovascular Medicine and Director\nof Duke-NUS\u2019 CVMD Programme, and a Senior Consultant at the National Heart\nCentre Singapore. \u201cThe combination of in-house experiments and large public\ndata repositories, together with the novel functional genomics approach we used\nto integrate various data types, provide a powerful tool to explore gene\nregulation.\u201d<\/p>\n\n\n\n

Professor\nPatrick Casey, Senior Vice Dean for Research at Duke-NUS, commented, \u201cOur ability\nto understand disease is being revolutionised by the availability of new\ntechnologies, whose power can best be realised by interdisciplinary teams\ncombined with the development of methods that can address previously\nintractable questions. As exemplified in this study, the best way to do this is\nby bringing together scientific and clinical expertise with cutting-edge\ntechnology.\u201d<\/p>\n\n\n\n

The researchers recommend future research to carefully\nreveal the interdependencies and cross-talks in the various stages of gene\nexpression in order to be able to develop a holistic view of the regulatory\nprocess contributing to the manifestation of disease.<\/p>\n
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The formation of excess fibrous tissue in the heart, which underlies several heart diseases, could be prevented by inhibiting specific proteins that bind to RNA while its code is being translated. Using cutting-edge technologies, researchers at Duke-NUS Medical School, Singapore, have developed the first genome-wide dataset on protein translation during fibroblast activation, revealing a network […]<\/p>\n","protected":false},"author":2,"featured_media":16817,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3],"tags":[],"class_list":["post-16816","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-news"],"featured_image_urls":{"full":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2019\/09\/illustration.png",1350,756,false],"thumbnail":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2019\/09\/illustration-200x200.png",200,200,true],"medium":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2019\/09\/illustration-300x168.png",300,168,true],"medium_large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2019\/09\/illustration-768x430.png",750,420,true],"large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2019\/09\/illustration-1024x573.png",750,420,true],"1536x1536":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2019\/09\/illustration.png",1350,756,false],"2048x2048":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2019\/09\/illustration.png",1350,756,false],"ultp_layout_landscape_large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2019\/09\/illustration.png",1200,672,false],"ultp_layout_landscape":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2019\/09\/illustration.png",870,487,false],"ultp_layout_portrait":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2019\/09\/illustration.png",600,336,false],"ultp_layout_square":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2019\/09\/illustration.png",600,336,false],"newspaper-x-single-post":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2019\/09\/illustration-760x490.png",760,490,true],"newspaper-x-recent-post-big":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2019\/09\/illustration-550x360.png",550,360,true],"newspaper-x-recent-post-list-image":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2019\/09\/illustration-95x65.png",95,65,true],"web-stories-poster-portrait":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2019\/09\/illustration.png",640,358,false],"web-stories-publisher-logo":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2019\/09\/illustration.png",96,54,false],"web-stories-thumbnail":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2019\/09\/illustration.png",150,84,false]},"author_info":{"info":["RevoScience"]},"category_info":"News<\/a>","tag_info":"News","comment_count":"0","_links":{"self":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts\/16816","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/comments?post=16816"}],"version-history":[{"count":0,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts\/16816\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/media\/16817"}],"wp:attachment":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/media?parent=16816"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/categories?post=16816"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/tags?post=16816"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}