Long noncoding RNA VENTHEART is required for cardiomyocyte specification and function
Long noncoding RNA VENTHEART is required for cardiomyocyte specification and function
ABSTRACT RationaleLong noncoding RNAs (lncRNAs) control cardiac gene expression during heart development and disease. It is accordingly plausible for the same lncRNA to regulate both cardiac development, as well as play a role in adult heart disease progression. lncRNA regulators of early cardiomyocyte (CM) lineage commitment have been identified and characterised, however those controlling later CM specification remain unknown. ObjectivesIn this study we identified a novel lncRNA required for CM specification, maturation and function, and also discovered its suggested relevance to heart disease. Methods and ResultsWe performed single cell RNA-seq on human embryonic stem cell derived cardiomyocytes at 2, 6 and 12 weeks of differentiation. Weighted correlation network analysis (WGCNA) identified core gene modules, including lncRNAs highly abundant and uniquely expressed in the human heart. A lncRNA (we call VENTHEART, VHRT) co-expressed with cardiac maturation and ventricular-specific genes MYL2 and MYH7, as well as in adult human ventricular tissue. CRISPR-mediated excision of VHRT led to impaired CM sarcomere formation, and loss of the CM specification gene program. VHRT knockdown (KD) in hESC-CMs confirmed its regulatory role for key cardiac contraction, calcium hemostasis and heart development genes, including MYH6 and RYR2. Functional evaluation after VHRT KD using impedance-based technology and action potential recordings, proved reduced contraction amplitude and loss of the ventricular-like action potential in CM, respectively. Through an integrative analysis of genome-wide association studies (GWAS), expression quantitative trait locus (eQTL) and gene co-expression network, we found VHRT to be co-regulated with core cardiac contractile genes, and the likely source of a heart failure genetic association signal overlapping the VHRT gene locus. Finally, VHRT KD and human failing heart transcriptome comparison validates the consistent downregulation again of cardiac contractile and calcium regulatory genes (P<0.05). ConclusionWe conclude that VHRT lncRNA is required for proper CM specification and function. Furthermore, reduced VHRT may contribute to the development or progression of human heart disease.
Foo Roger S.、Bin Chen Gao、Tan Wilson L.W.、Ackers-Johnson Matthew Andrew、Ilmari Autio Matias、Lim Bing、Wei Heming、Anene-Nzelu Chukwuemeka George、Jonsson Malin K.B.、Walentinsson Anna、Dashi Albert、Iyer Vidhya Vardharajan、Hartman Robin J.G.、Tiang Zenia、Pan Bangfen、Stenzig Justus
Cardiovascular Disease Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore||Cardiovascular Research Institute, National University Healthcare Systems||Genome Institute of Singapore, Agency for Science, Technology and ResearchGenome Institute of Singapore, Agency for Science, Technology and ResearchCardiovascular Disease Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore||Cardiovascular Research Institute, National University Healthcare Systems||Genome Institute of Singapore, Agency for Science, Technology and ResearchCardiovascular Disease Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore||Cardiovascular Research Institute, National University Healthcare Systems||Genome Institute of Singapore, Agency for Science, Technology and ResearchCardiovascular Research Institute, National University Healthcare Systems||Genome Institute of Singapore, Agency for Science, Technology and ResearchSana BiotechnologyNational Heart Research Institute Singapore (NHRIS), National Heart Centre SingaporeCardiovascular Disease Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore||Cardiovascular Research Institute, National University Healthcare Systems||Genome Institute of Singapore, Agency for Science, Technology and ResearchCardiovascular Disease Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore||Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&DTranslational Science & Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZenecaCardiovascular Disease Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore||Cardiovascular Research Institute, National University Healthcare Systems||Genome Institute of Singapore, Agency for Science, Technology and ResearchBioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D||Uppsala UniversityGenome Institute of Singapore, Agency for Science, Technology and Research||University of UtrechtCardiovascular Disease Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore||Cardiovascular Research Institute, National University Healthcare Systems||Genome Institute of Singapore, Agency for Science, Technology and ResearchCardiovascular Disease Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore||Cardiovascular Research Institute, National University Healthcare Systems||Genome Institute of Singapore, Agency for Science, Technology and ResearchUniversity Medical Center Hamburg-Eppendorf
基础医学生物科学研究方法、生物科学研究技术分子生物学
single cell RNAseqtranscriptomicstem cell derived cardiomyocyteslncRNAcardiac myocyte specification and maturationcardiomyocyte contractioncalcium signalingheart disease.
Foo Roger S.,Bin Chen Gao,Tan Wilson L.W.,Ackers-Johnson Matthew Andrew,Ilmari Autio Matias,Lim Bing,Wei Heming,Anene-Nzelu Chukwuemeka George,Jonsson Malin K.B.,Walentinsson Anna,Dashi Albert,Iyer Vidhya Vardharajan,Hartman Robin J.G.,Tiang Zenia,Pan Bangfen,Stenzig Justus.Long noncoding RNA VENTHEART is required for cardiomyocyte specification and function[EB/OL].(2025-03-28)[2025-08-03].https://www.biorxiv.org/content/10.1101/2021.02.01.429136.点此复制
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