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

Abstract

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 (IncRNAs) 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 IncRNAs 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 IncRNAs 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 IncRNAs.

Non-coding RNAs in muscle differentiation and musculoskeletal disease

“…Interestingly, the alteration of H19 and IGF2 coexpression is associated with RMS in humans (89). In addition to eRNAs in skeletal muscle, many eRNAs have been identified in cardiac development that are deregulated in several different cardiomyopathies (90,91). Overall, these findings place eRNAs at the top of a molecular hierarchy regulating myogenesis and predict their possible participation in muscle diseases as a result of mutations and/or altered expression (92).…”

Long Noncoding RNA PVT1 Promotes Non–Small Cell Lung Cancer Cell Proliferation through Epigenetically Regulating LATS2 Expression

“…LncRNAs were once regarded as transcriptional "noise" or cloning artifacts because of their absence of protein-encoding ability (6). Emerging evidence has indicated that aberrant expression of lncRNAs is associated with numerous diseases, including diabetes (7,8). Importantly, lncRNAs were shown to act as regulators of tumorigenesis via participating in biologic processes, such as modulation of apoptosis, proliferation, drug resistance, and the epithelial-mesenchymal transition process (9)(10)(11)(12).…”

Interactions between microRNAs and long non-coding RNAs in cardiac development and repair

“…Hundreds of lncRNAs have been found to be cardiac-specific during development or in pathological conditions, although their function needs further studies [50,51]. Forty lncRNAs involved in the lateral plate mesoderm formation and cardiomyocyte differentiation were observed to be differentially expressed during embryonic carcinoma cell differentiation into cardiac myocytes [52].…”

“…-132 and -172) expressed during cardiomyocyte differentiation of murine embryonic stem cells [50]. Four of these elncRNAs (mm67, -85, -130 and -132) appear to be evolutionary conserved in humans.…”

“…Moreover, another lcnRNA has been found associated with cardiomyocytes in subjects affected by dilated cardiomyopathy, named Novlnc6. Although its role is not yet elucidated, inhibition experiments using Gapmers display that down-regulation of Novlnc6, a reduction in the expression of Bmp10 and Nkx2.5 at mRNA level is observed [50].…”