{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:02:02Z","timestamp":1791316922296,"version":"4.3.1"},"reference-count":5,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T00:00:00Z","timestamp":1743724800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"BHF\/DHF\/DZHK"},{"name":"Heart Foundation of Australia Future Leader Fellowship","award":["102036"],"award-info":[{"award-number":["102036"]}]},{"DOI":"10.13039\/501100000923","name":"Australian Research Council","doi-asserted-by":"publisher","award":["DP210102134"],"award-info":[{"award-number":["DP210102134"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["2021155"],"award-info":[{"award-number":["2021155"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["2038886"],"award-info":[{"award-number":["2038886"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>The highly conserved long non-coding RNA (lncRNA) MIR505HG has been primarily recognized as a precursor for microRNAs (miR)-424 and miR-503. However, studies have since demonstrated that MIR503HG has distinct functions from its associated miRNAs, playing important roles in cell proliferation, invasion, apoptosis, and differentiation. While these miRNAs are known to influence cardiomyocyte differentiation, the specific role of MIR503HG in heart development remains unexplored. We seek to determine how MIR503HG deletion impacts ventricular chamber development and to identify underlying molecular mechanisms.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>To study the role of the lncRNA in vivo, we generated a functional MIR503HG knockout mouse model (MIR503HG\u2212\/\u2212) using a synthetic polyadenylation signal to terminate MIR503HG transcription without affecting miR-424\/503 expression. We performed morphological analyses on embryonic and adult hearts using microCT along with cardiac functional analysis via transthoracic echocardiography. We further apply single-nuclei RNA sequencing (snRNA-seq) on adult hearts to identify potential molecular mechanisms underlying the observed phenotypes. Functional deletion of MIR503HG alone was associated with reduced compact myocardium thickness and increased trabecular myocardium in the left ventricle (LV) at embryonic day 17.5 compared to wild-type mice, indicating a LV non-compaction (LVNC) phenotype. Moreover, adult MIR503HG\u2212\/\u2212 mutant hearts showed increased trabecular complexity, impaired LV relaxation, and mitral valve regurgitation. SnRNA-seq further revealed altered expression of several genes associated with cardiomyocyte function and LVNC, including Actc1, Mib1, Mybpc3, and Myh7. Lastly, Notch1 activity was also significantly increased in mutant hearts which has been previously associated with LVNC.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>MIR503HG plays a role in ventricular chamber development, and its deletion leads to an LVNC phenotype independent of the miRNA cluster within its locus, highlighting its importance in cardiac development and disease. We further suggest that abnormal Notch1 activity may underpin the LVNC phenotype presented.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf043","type":"journal-article","created":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T20:49:40Z","timestamp":1743367780000},"page":"988-991","source":"Crossref","is-referenced-by-count":10,"title":["Loss of conserved long non-coding RNA MIR503HG leads to altered NOTCH pathway signalling and left ventricular non-compaction cardiomyopathy"],"prefix":"10.1093","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6481-6875","authenticated-orcid":false,"given":"Jo\u00e3o P","family":"Monteiro","sequence":"first","affiliation":[{"name":"Centre for Cardiovascular Science, Queen\u2019s Medical Research Institute, University of Edinburgh , 47 Little France Crescent, Edinburgh EH16 4TJ ,","place":["UK"]},{"name":"Division of Cardiovascular Medicine, Stanford University School of Medicine , Stanford, CA 94305 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diptarka","family":"Saha","sequence":"additional","affiliation":[{"name":"Australian Regenerative Medicine Institute, 15 Innovation Walk, Monash University , Clayton, VIC 3800 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8584-8048","authenticated-orcid":false,"given":"Ana-Mishel","family":"Spiroski","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Science, Queen\u2019s Medical Research Institute, University of Edinburgh , 47 Little France Crescent, Edinburgh EH16 4TJ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saiba","family":"Mahesh","sequence":"additional","affiliation":[{"name":"Australian Regenerative Medicine Institute, 15 Innovation Walk, Monash University , Clayton, VIC 3800 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2790-6606","authenticated-orcid":false,"given":"Peter","family":"Kaltzis","sequence":"additional","affiliation":[{"name":"Australian Regenerative Medicine Institute, 15 Innovation Walk, Monash University , Clayton, VIC 3800 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhijit","family":"Nadavallil","sequence":"additional","affiliation":[{"name":"Australian Regenerative Medicine Institute, 15 Innovation Walk, Monash University , Clayton, VIC 3800 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3837-1865","authenticated-orcid":false,"given":"Vaibhao","family":"Janbandhu","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute , Darlinghurst, NSW 2010 ,","place":["Australia"]},{"name":"School of Clinical Medicine, UNSW Sydney , Kensington, NSW 2052 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J","family":"Murray","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute , Darlinghurst, NSW 2010 ,","place":["Australia"]},{"name":"School of Clinical Medicine, UNSW Sydney , Kensington, NSW 2052 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2186-8274","authenticated-orcid":false,"given":"Francesco","family":"Severi","sequence":"additional","affiliation":[{"name":"Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh , Edinburgh EH16 4UU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2121-7068","authenticated-orcid":false,"given":"Azzurra Laura","family":"De Pace","sequence":"additional","affiliation":[{"name":"Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh , Edinburgh EH16 4UU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"S\u00e1nchez-Esteban","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Science, Queen\u2019s Medical Research Institute, University of Edinburgh , 47 Little France Crescent, Edinburgh EH16 4TJ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2900-5780","authenticated-orcid":false,"given":"Julie","family":"Rodor","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Science, Queen\u2019s Medical Research Institute, University of Edinburgh , 47 Little France Crescent, Edinburgh EH16 4TJ 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Institute, University of Edinburgh , 47 Little France Crescent, Edinburgh EH16 4TJ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7320-300X","authenticated-orcid":false,"given":"Adrian","family":"Thomson","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Science, Queen\u2019s Medical Research Institute, University of Edinburgh , 47 Little France Crescent, Edinburgh EH16 4TJ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1041-1781","authenticated-orcid":false,"given":"Patrick W F","family":"Hadoke","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Science, Queen\u2019s Medical Research Institute, University of Edinburgh , 47 Little France Crescent, Edinburgh EH16 4TJ 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Regeneration and Repair, University of Edinburgh , Edinburgh EH16 4UU ,","place":["UK"]},{"name":"MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh , Edinburgh EH4 2XU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00f3nal","family":"O\u2019Carroll","sequence":"additional","affiliation":[{"name":"Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh , Edinburgh EH16 4UU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7645-9067","authenticated-orcid":false,"given":"Thomas","family":"Quertermous","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Stanford University School of Medicine , Stanford, CA 94305 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9950-9792","authenticated-orcid":false,"given":"Richard 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Medical Research Institute, University of Edinburgh , 47 Little France Crescent, Edinburgh EH16 4TJ ,","place":["UK"]},{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, 6229 HX Maastricht, The \u00a0","place":["Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,4,4]]},"reference":[{"key":"2025070809315143900_cvaf043-B1","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1161\/CIRCRESAHA.120.318124","article-title":"MIR503HG loss promotes endothelial-to-mesenchymal transition in vascular disease","volume":"128","author":"Monteiro","year":"2021","journal-title":"Circ Res"},{"key":"2025070809315143900_cvaf043-B2","doi-asserted-by":"crossref","first-page":"9551","DOI":"10.1073\/pnas.1608256113","article-title":"miR-322\/-503 cluster is expressed in the earliest cardiac progenitor cells and drives cardiomyocyte 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Engl"}],"container-title":["Cardiovascular Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/cardiovascres\/advance-article-pdf\/doi\/10.1093\/cvr\/cvaf043\/62861160\/cvaf043.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cardiovascres\/article-pdf\/121\/7\/988\/62861160\/cvaf043.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cardiovascres\/article-pdf\/121\/7\/988\/62861160\/cvaf043.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T13:32:00Z","timestamp":1751981520000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cardiovascres\/article\/121\/7\/988\/8106288"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,4]]},"references-count":5,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,4,4]]},"published-print":{"date-parts":[[2025,7,8]]}},"URL":"https:\/\/doi.org\/10.1093\/cvr\/cvaf043","relation":{},"ISSN":["0008-6363","1755-3245"],"issn-type":[{"value":"0008-6363","type":"print"},{"value":"1755-3245","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,6]]},"published":{"date-parts":[[2025,4,4]]}}}