Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease
| Autor: | Rory Johnson, Rudi Micheletti, Iole Pezzuto, Alexandre Sarre, Michael Alexanian, Frédéric Burdet, Dalit May, Christine Gonzales, Jérôme Dauvillier, Thierry Pedrazzini, Samir Ounzain, Razan Sheta, Matthew J. Blow, Len A. Pennacchio, Mohamed Nemir |
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| Rok vydání: | 2014 |
| Předmět: |
Polyadenylation
Heart Diseases Long noncoding RNA (lncRNAs) Primary Cell Culture Gene Expression Muscle Proteins Heart failure Enhancer RNAs 030204 cardiovascular system & hematology Biology Article Gene regulatory networks 03 medical and health sciences Mice Cardiac development 0302 clinical medicine Gene expression Enhancers Animals Humans Enhancer Gene Transcription factor Molecular Biology Cells Cultured Embryonic Stem Cells 030304 developmental biology Regulation of gene expression Genetics 0303 health sciences Gene knockdown Gene Expression Regulation Developmental Heart Gene regulation Enhancer Elements Genetic RNA Long Noncoding Long noncoding RNA (IncRNAs) Cardiology and Cardiovascular Medicine |
| Zdroj: | Current Therapeutic Research-Clinical and Experimental Journal of Molecular and Cellular Cardiology, vol. 76, pp. 55-70 Journal of molecular and cellular cardiology |
| DOI: | 10.1016/j.yjmcc.2014.08.009 |
| Popis: | © 2014 . The key information processing units within gene regulatory networks are enhancers. Enhancer activity is associated with the production of tissue specific noncoding RNAs yet the existence of such transcripts during cardiac development has not been established. Using an integrated genomic approach we demonstrate that fetal cardiac enhancers generate long noncoding RNAs (lncRNAs) during cardiac differentiation and morphogenesis. Enhancer expression correlates with the emergence of active enhancer chromatin states the initiation of RNA polymerase II at enhancer loci and expression of target genes. Orthologous human sequences are also transcribed in fetal human hearts and cardiac progenitor cells. Through a systematic bioinformatic analysis we identified and characterized for the first time a catalog of lncRNAs that are expressed during embryonic stem cell differentiation into cardiomyocytes and associated with active cardiac enhancer sequences. RNA sequencing demonstrates that many of these transcripts are polyadenylated multi exonic long noncoding RNAs. Moreover knockdown of two enhancer associated lncRNAs resulted in the specific downregulation of their predicted target genes. Interestingly the reactivation of the fetal gene program a hallmark of the stress response in the adult heart is accompanied by increased expression of fetal cardiac enhancer transcripts. Altogether these findings demonstrate that the activity of cardiac enhancers and expression of their target genes are associated with the production of enhancer derived lncRNAs. •Fetal cardiac enhancers are transcribed generating enhancer derived lncRNAs. |
| Databáze: | OpenAIRE |
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