serval:BIB_12D4EA4E6C03
Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease.
10.1016/j.yjmcc.2014.08.009
000344202800007
25149110
Ounzain
S.
author
Pezzuto
I.
author
Micheletti
R.
author
Burdet
F.
author
Sheta
R.
author
Nemir
M.
author
Gonzales
C.
author
Sarre
A.
author
Alexanian
M.
author
Blow
M.J.
author
May
D.
author
Johnson
R.
author
Dauvillier
J.
author
Pennacchio
L.A.
author
Pedrazzini
T.
author
article
2014
Journal of Molecular and Cellular Cardiology
1095-8584
0022-2828
journal
76
55-70
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.
eng
60_published
true
peer-reviewed
University of Lausanne
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