Editorial
Cardiovascular Research (2008) 79, 551–552
doi:10.1093/cvr/cvn189
MicroRNAs: components of an integrated system
controlling cardiac development, physiology,
and disease pathogenesis
Gianluigi Condorelli1,2* and Stefanie Dimmeler3
1
Division of Cardiology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, San Diego,
CA 92093-0641, USA; 2Scientific and Technology Pole, Istituto di Ricovero e Cura a Carattere Scientifico Multimedica, Via
Fantoli 16/15, Milan 20138, Italy; and 3Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt,
Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
Online publish-ahead-of-print 9 July 2008
See reviews in this series by Fazi and Nervi,21 Thum
et al.,22 Yang et al.,23 and Urbich et al. 24
Protein-encoding sequences comprise ,1.5% of the human
genome.1 Nevertheless, a considerable fraction (90%) of
the genome is effectively transcribed.2 Therefore, most of
the transcriptional output of the genome of higher organisms seems to consist of non-coding (nc) RNAs, i.e. RNA
that is not translated into a protein end product.3 It is
now clear that much of this genomic output is not just transcriptional background noise of ‘junk’ DNA but an intricate
RNA-based network constituting a level of regulation that
appears as important as posttranscriptional protein modification. Only a limited number of ncRNA species predominantly maintaining basic biochemical processes, such as
ribosomal RNA and transfer RNA, have been analysed in
depth, but other types of ncRNAs have now been identified
and are being studied.4 These ncRNAs regulate the gene
expression process at many of its steps, from the epigenetic
level down to translation, through a variety of mechanisms
(Figure 1).5 ncRNA has also been implicated in surprising
areas, such as the integrity of cellular structure,6 and
many other fascinating functions probably await discovery.
The thought that RNA might be involved in the control of
gene expression first arose in the late 1960s: RNAs were
hypothesized to specify which genes were turned on and
off in eukaryotic cells with a mechanism based on the basepairing rules of Watson and Crick.7 Nonetheless, this theory
was buried in oblivion probably as a result of the exciting
discovery of protein transcription factors. However, in the
past few decades, convincing evidence has emerged that
RNA is, in fact, more than simply an intermediary between
DNA and protein. Several classes of ncRNA are now known
that have a fundamental role in the control of gene
The opinions expressed in this article are not necessarily those of
the Editors of Cardiovascular Research or of the European Society of
Cardiology.
* Corresponding author. Tel: þ1 8585343347; fax: þ1 8585343347.
E-mail address: [email protected]
expression: whereas long ncRNAs control dosage compensation and genomic imprinting,5 one class of small ncRNAs,
micro (mi)RNAs, is predicted to regulate at least one-third
of all human genes.8 These approximately 22 nucleotide
ncRNAs, together with their associated proteins, act in
gene silencing pathways through the regulation of mRNA
stability and protein translation.
Unexpected findings had been obtained in experiments
with plants during the late 1980s and early 1990s in which
certain genes were to be overexpressed: occasionally,
instead of the expected increased gene expression, downregulation was observed.9–11 This finding was later confirmed in the nematode, Caenorhabditis elegans, the
species in which key breakthroughs in RNA silencing would
be made: for example, that double-stranded (ds)RNA is
the trigger for mRNA destruction12 and that dsRNA is converted into small RNAs, called short-interfering (si)RNA, to
mediate silencing phenomena with a mechanism termed
RNA interference.13
In parallel with the discovery of how exogenously introduced RNA, i.e. siRNA, could mediate gene expression,
reports were being published that would pave the way for
the discovery of their endogenous counterpart, namely
miRNA. Two independent studies published in 1993 reported
that lin-4, a heterochronic gene controlling the timing of
development of nematodes, does not code for a protein but
produces small RNA transcripts, complementary to the
3’-untranslated region of lin-14 mRNA.14,15 The subsequent
inhibition of lin-14 translation provided the explanation of
the mechanism of the heterochronic switch. Several years
later, the connection between miRNAs and siRNAs was made
when Dicer, the enzyme converting dsRNA into siRNAs, was
shown to convert pre-miRNAs into mature miRNAs.16–18
Since then, the function of miRNAs in developmental
biology of higher organisms, including mammals, has been
established.19 Moreover, a remarkable number of publications have linked miRNA to physiological processes and
to pathologies such as cancer.20 In comparison to other
fields, the elucidation of the role of miRNAs in the cardiovascular system is in its infancy, but the studies published
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2008.
For permissions please email: [email protected].
552
Editorial
this machinery. Future studies will increase our awareness
of the complexity of gene expression control and of the
role played by miRNA in particular.
References
Figure 1 Outline of some ncRNA functions. The central dogma of the flow of
genetic information from DNA to RNA to proteins (thick black lines) in which
only proteins control gene expression (thin black line) has been integrated
with a complex array of ncRNAs acting in a networking system controlling
gene expression at many of its steps (dashed lines). miRNA (bold) is only
one component. RNAs: mi, micro; nc, non-coding; pi, piwi; rasi,
repeat-associated small interfering; si, short interfering; sn, small nuclear;
sno, small nucleolar; SRP, signal recognition particle; TF, transcription factor.
to date underscore the fundamental role that miRNA has on
many aspects of biology of the heart and vasculature.
In this review focus of the Journal, four review articles
highlight the current understanding we have gained in the
role of miRNA in cardiovascular biology. First, Fazi and
Nervi21 detail miRNA biogenesis and function and demonstrate
the importance of miRNA in the development of muscle,
nervous, and blood tissues. Then, Thum et al. 22 summarize
the role of miRNA in cardiac developmental biology and in a
fundamental aspect underlying heart diseases, i.e. hypertrophic growth. Yang et al.23 focus on the role of miRNAs in
electropathophysiology, another important area of heart
biology. Finally, Urbich et al.24 report on aspects of vascular
biology, which so far have not been specifically translated to
the heart but that are nonetheless essential in the development and treatment of ischaemic diseases.
It is now obvious that the complexity of an organism is
not limited to the number of different protein-coding
genes and the interaction of their products but, rather, to
the exquisite intricacies of the entire interactome, which
includes ncRNAs as an integral and probably prevailing
part.25 In this complex regulatory network, microRNAs are
just one of the players. The few recent studies reviewed
in this review focus just start to scrape the surface of this
control system in the heart. Much more work lies ahead
not only to understand the role of miRNAs and the regulation
of their expression and maturation but also to discover the
function of other ncRNAs in the heart. The identification
of these components and the elucidation of mechanisms
of these complex interactions require the development of
powerful high-throughput technology and computation
algorithms capable of integrating data from all parts of
1. International Human Genome Sequencing Consortium. Initial sequencing
and analysis of the human genome. Nature 2001;409:860–921.
2. ENCODE Project Consortium. Identification and analysis of functional
elements in 1% of the human genome by the ENCODE pilot project.
Nature 2007;447:799–816.
3. Mattick JS. Non-coding RNAs: the architects of eukaryotic complexity.
EMBO Rep 2001;2:986–991.
4. Mattick JS, Makunin IV. Non-coding RNA. Hum Mol Genet 2006;15:
R17–R29.
5. Amaral PP, Dinger ME, Mercer TR, Mattick JS. The eukaryotic genome as
an RNA machine. Science 2008;319:1787–1789.
6. Kloc M, Wilk K, Vargas D, Shirato Y, Bilinski S, Etkin LD. Potential
structural role of non-coding and coding RNAs in the organization of
the cytoskeleton at the vegetal cortex of Xenopus oocytes. Development
2005;132:3445–3457.
7. Britten RJ, Davidson EH. Gene regulation for higher cells: a theory.
Science 1969;165:349–357.
8. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by
adenosines, indicates that thousands of human genes are microRNA
targets. Cell 2005;120:15–20.
9. Matzke MA, Primig M, Trnovsky J, Matzke AJ. Reversible methylation and
inactivation of marker genes in sequentially transformed tobacco plants.
EMBO J 1989;8:643–649.
10. Napoli C, Lemieux C, Jorgensen R. Introduction of a chimeric chalcone
synthase gene into petunia results in reversible co-suppression of
homologous genes in trans. Plant Cell 1990;2:279–289.
11. van der Krol AR, Mur LA, Beld M, Mol JMN, Stuitji AR. Flavonoid genes
in petunia: addition of a limited number of gene copies may lead to a
suppression of gene expression. Plant Cell 1990;2:291–299.
12. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and
specific genetic interference by double-stranded RNA in Caenorhabditis
elegans. Nature 1998;391:806–811.
13. Hamilton AJ, Baulcombe DC. A species of small antisense RNA in posttranscriptional gene silencing in plants. Science 1999;286:950–952.
14. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4
encodes small RNAs with antisense complementarity to lin-14. Cell.1993;
75:843–854.
15. Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in
C. elegans. Cell 1993;75:855–862.
16. Grishok A, Pasquinelli AE, Conte D, Li N, Parrish S, Ha I et al. Genes and
mechanisms related to RNA interference regulate expression of the small
temporal RNAs that control C. elegans developmental timing. Cell 2001;
106:23–34.
17. Hutvágner G, McLachlan J, Pasquinelli AE, Bálint E, Tuschl T, Zamore PD.
A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 2001;293:834–838.
18. Ketting RF, Fischer SEJ, Bernstein E, Sijen T, Hannon GJ, Plasterk RHA.
Dicer functions in RNA interference and in synthesis of small RNA involved
in developmental timing in C. elegans. Genes Dev 2001;15:2654–2659.
19. Blakaj A, Lin H. Piecing together the mosaic of early mammalian development through microRNAs. J Biol Chem 2008;283:9505–9508.
20. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E et al. Frequent
deletions and down-regulation of microRNA genes miR15 and miR16 at
13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 2002;
99:15524–15529.
21. Fazi F, Nervi C. MicroRNA: basic mechanisms and transcriptional
regulatory networks for cell fate determination. Cardiovasc Res 2008;
79:553–561.
22. Thum T, Catalucci D, Bauersachs J. MicroRNAs: novel regulators in cardiac
development and disease. Cardiovasc Res 2008;79:562–570.
23. Yang B, Lin H, Xiao J, Lu Y, Wang Z. Control of cardiac excitability by
microRNAs. Cardiovasc Res 2008;79:571–580.
24. Urbich C, Kuehbacher A, Dimmeler S. Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovasc Res 2008;79:581–588.
25. Costa FF. Non-coding RNAs: Lost in translation? Gene 2007;386:1–10.