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Title: Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease

Abstract

We report here that 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 enhancersmore » and expression of their target genes are associated with the production of enhancer-derived lncRNAs.« less

Authors:
 [1];  [1];  [1];  [2];  [1];  [1];  [1];  [3];  [1];  [4];  [4];  [5];  [2];  [4];  [1]
  1. Univ. of Lausanne Medical School, Lausanne (Switzerland)
  2. Univ. of Lausanne Medical School, Lausanne (Switzerland). VitalIT, Swiss Institute of Bioinformatics
  3. Univ. of Lausanne Medical School, Lausanne (Switzerland). Cardiovascular Assessment Facility
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); DOE Joint Genome Inst., Walnut Creek, CA (United States)
  5. Centre for Genomic Regulation, Barcelona (Spain)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1257346
Grant/Contract Number:
AC02-05CH11231; R01HG003988
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Molecular and Cellular Cardiology
Additional Journal Information:
Journal Volume: 76; Journal Issue: C; Journal ID: ISSN 0022-2828
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Ounzain, Samir, Pezzuto, Iole, Micheletti, Rudi, Burdet, Frédéric, Sheta, Razan, Nemir, Mohamed, Gonzales, Christine, Sarre, Alexandre, Alexanian, Michael, Blow, Matthew J., May, Dalit, Johnson, Rory, Dauvillier, Jérôme, Pennacchio, Len A., and Pedrazzini, Thierry. Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease. United States: N. p., 2014. Web. doi:10.1016/j.yjmcc.2014.08.009.
Ounzain, Samir, Pezzuto, Iole, Micheletti, Rudi, Burdet, Frédéric, Sheta, Razan, Nemir, Mohamed, Gonzales, Christine, Sarre, Alexandre, Alexanian, Michael, Blow, Matthew J., May, Dalit, Johnson, Rory, Dauvillier, Jérôme, Pennacchio, Len A., & Pedrazzini, Thierry. Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease. United States. doi:10.1016/j.yjmcc.2014.08.009.
Ounzain, Samir, Pezzuto, Iole, Micheletti, Rudi, Burdet, Frédéric, Sheta, Razan, Nemir, Mohamed, Gonzales, Christine, Sarre, Alexandre, Alexanian, Michael, Blow, Matthew J., May, Dalit, Johnson, Rory, Dauvillier, Jérôme, Pennacchio, Len A., and Pedrazzini, Thierry. Tue . "Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease". United States. doi:10.1016/j.yjmcc.2014.08.009. https://www.osti.gov/servlets/purl/1257346.
@article{osti_1257346,
title = {Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease},
author = {Ounzain, Samir and Pezzuto, Iole and Micheletti, Rudi and Burdet, Frédéric and Sheta, Razan and Nemir, Mohamed and Gonzales, Christine and Sarre, Alexandre and Alexanian, Michael and Blow, Matthew J. and May, Dalit and Johnson, Rory and Dauvillier, Jérôme and Pennacchio, Len A. and Pedrazzini, Thierry},
abstractNote = {We report here that 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.},
doi = {10.1016/j.yjmcc.2014.08.009},
journal = {Journal of Molecular and Cellular Cardiology},
number = C,
volume = 76,
place = {United States},
year = {Tue Aug 19 00:00:00 EDT 2014},
month = {Tue Aug 19 00:00:00 EDT 2014}
}

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