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microRNA
REVIEWS
Richard
J. Jackson & Nancy Standart
Sci STKE. 2007(367): re1
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK Several thousand human
genes, amounting to aboutone-third of the whole genome, are potential
targetsfor regulation by the several hundred microRNAs(miRNAs) encoded
in the genome. The regulationoccurs posttranscriptionally and involves
the ~21-nucleotide miRNAinteracting with a target site in themRNAthat
generally has imperfect complementarityto the miRNA. The target sites
are almost invariablyin the 3′-untranslated region of the messenger
RNA(mRNA), often in multiple copies. Metazoan miRNAswere previously
thought to down-regulate proteinexpression by inhibiting target
mRNAtranslation atsome stage after the translation initiation step,
with-out much effect on mRNAabundance. However,recent studies have
questioned these suppositions.With some targets, an increase in the
rate of mRNAdegradation by the normal decay pathway con-tributes to the
decrease in protein expression.miRNAs can also inhibit translation
initiation, specif-ically the function of the cap-binding initiation
factor,eIF4E. Repressed target mRNAs as well as miRNAsthemselves
accumulate in cytoplasmic foci knownas P-bodies, where many enzymes
involved in mRNAdegradation are concentrated. However, P-bodiesmay also
serve as repositories for the temporary andreversible storage of
untranslated mRNA, and reduc-ing the expression (knockdown) of several
distinctP-body protein components can alleviate miRNA-mediated
repression of gene expression.
MicroRNA: past and present Yang Wang, Heidi M. Stricker, Deming Gou, Lin Liu Department of Physiological Sciences, Oklahoma State University, Stillwater, OK, 74078 Frontiers in Bioscience 12, 2316-2329, January 1, 2007 MicroRNAs (miRNAs) are
~22 nucleotide (nt) non-coding RNAs that participate in gene
regulation. MiRNAs confer their regulation at a
post-transcriptional level, where they either cleave or repress
translation of mRNAs. Over 3000 identified mature miRNAs exist in
species ranging from plants to humans, suggesting that they are ancient
players in gene regulation. A relatively small number of miRNAs
have been experimentally tested for their function. Of those
tested, functions including cell differentiation, proliferation,
apoptosis, anti-viral defense and cancer have been proposed.
Improved software programs are now able to predict the targets of
miRNAs in a more efficient manner, thus facilitating the elucidation of
miRNA function. Furthermore, methods such as real-time PCR and
microarray have been enhanced for studying miRNA expression.
Using these tools, scientists are able to discover novel functions for
miRNAs. It is possible that miRNAs will be revealed as having a
role in virtually every aspect of gene regulation. This review
guides readers through the biogenesis of miRNAs, their mechanism of
action on their target mRNAs, the functional outcomes of their action
on mRNAs and the current techniques to investigate these processes.
Mechanisms
of post-transcriptional regulation by microRNAs: are the answers in
sight?
MicroRNAs constitute a large family of small,
approximately 21-nucleotide-long, non-coding RNAs that have emerged as
key post-transcriptional regulators of gene expression in metazoans and
plants. In mammals, microRNAs are predicted to control the activity of
approximately 30% of all protein-coding genes, and have been shown to
participate in the regulation of almost every cellular process
investigated so far. By base pairing to mRNAs, microRNAs mediate
translational repression or mRNA degradation. This Review summarizes
the current understanding of the mechanistic aspects of
microRNA-induced repression of translation and discusses some of the
controversies regarding different modes of microRNA function.Filipowicz W, Bhattacharyya SN, Sonenberg N. Friedrich Miescher Institute for Biomedical Research, 4002 Basel, Switzerland. witold.filipowicz@fmi.ch Nat Rev Genet. 2008 Feb;9(2): 102-114. microRNAs
in vertebrate physiology and human disease
Over the past five years, the importance of a diverse
class of 18-24 nucleotide RNA molecules, known as microRNAs (miRNAs)
has increasingly been recognized. These highly conserved RNAs regulate
the stability and translational efficiency of complementary target
messenger RNAs. The human genome is now predicted to encode nearly
1,000 miRNAs that likely regulate at least one third of all human
transcripts. Despite rapid progress in miRNA discovery, the physiologic
functions of only a small number have been definitively established. In
this review, we discuss the principles of miRNA function that have
emerged from the studies performed thus far in vertebrates. We also
discuss known and potential roles for miRNAs in human disease states
and discuss the influence of human genetic variation on miRNA-mediated
regulation.Chang TC, Mendell JT. The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA. Annu Rev Genomics Hum Genet. 2007;8: 215-239. Illuminating
the silence: understanding the structure and function of small RNAs
RNA interference (RNAi) is triggered by double-stranded
RNA helices that have been introduced exogenously into cells as small
interfering (si)RNAs or that have been produced endogenously from small
non-coding RNAs known as microRNAs (miRNAs). RNAi has become a standard
experimental tool and its therapeutic potential is being aggressively
harnessed. Understanding the structure and function of small RNAs, such
as siRNAs and miRNAs, that trigger RNAi has shed light on the RNAi
machinery. In particular, it has highlighted the assembly and function
of the RNA-induced silencing complex (RISC), and has provided
guidelines to efficiently silence genes for biological research and
therapeutic applications of RNAi.Tariq M. Rana NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 8 | JANUARY 2007 | 23 Boyd SD. Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305-2297, USA. Lab Invest. 2008 Jun;88(6): 569-578 MicroRNAs are a class of
recently discovered small RNA molecules that regulate other
genes in the human genome. Studies in human cells and model organisms
have begun to reveal the mechanisms of microRNA
activity, and the wide range of normal physiological
functions they influence. Their alteration in pathologic statesfrom
cancer to cardiovascular disease is also increasingly clear. A review
of current evidence for the role of these molecules in
human health and disease will be helpful to
pathologists and medical researchers as the fascinating story of these
small regulators continues to unfold.
The regulation of genes andgenomes by small RNAsVictor Ambros & Xuemei Chen Development 134, 1635-1641(2007) A recent Keystone
Symposium on ‘MicroRNAs and siRNAs:Biological Functions and Mechanisms’
was organized by DavidBartel and Shiv Grewal (and was held in
conjunction with ‘RNAifor Target Validation and as a Therapeutic’,
organized byStephen Friend and John Maraganore). The ‘MicroRNAs
andsiRNAs’ meeting brought together scientists working on
diversebiological aspects of small regulatory RNAs, includingmicroRNAs,
small interfering RNAs (siRNAs) and Piwi-interactingRNAs (piRNAs and
rasiRNAs). Among the themes discussed werethe diversity of small
regulatory RNAs and their developmentalfunctions, their biogenesis, the
identification of their regulatorytargets, their mechanisms of action,
and their roles in theelaboration of multicellular complexity.
MicroRNAs
in Gene Regulation: When the Smallest Governs It All
Encoded by the genome of most eukaryotes examined so far,
microRNAs (miRNAs) are small ~21-nucleotide (nt) noncoding RNAs
(ncRNAs) derived from a biosynthetic cascade involving sequential
processing steps executed by the ribonucleases (RNases) III Drosha and
Dicer. Following their recent identification, miRNAs have rapidly taken
the center stage as key regulators of gene expression. In this review,
we will summarize our current knowledge of the miRNA biosynthetic
pathway and its protein components, as well as the processes it
regulates via miRNAs, which are known to exert a variety of biological
functions in eukaryotes. Although the relative importance of miRNAs
remains to be fully appreciated, deregulated protein expression
resulting from either dysfunctional miRNA biogenesis or abnormal
miRNA-based gene regulation may represent a key etiologic factor in
several, as yet unidentified, diseases. Hence is our need to better
understand the complexity of the basic mechanisms underlying miRNA
biogenesis and function.Ouellet DL, Perron MP, Gobeil LA, Plante P, Provost P. J Biomed Biotechnol. 2006;2006(4): 69616. Clustering
and conservation patterns of human microRNAs
MicroRNAs (miRNAs) are approximately 22 nt-long non-coding
RNA molecules, believed to play important roles in gene
regulation. We present a comprehensive analysis of the
conservation and clustering patterns of known miRNAs in human. We show
that human miRNA gene clustering is significantly higher than expected
at random. A total of 37% of the known human miRNA
genes analyzed in this study appear in clusters of two
or more with pairwise chromosomal distances of at most 3000
nt. Comparison of the miRNA sequences with their homologs in four other
organisms reveals a typical conservation pattern,
persistent throughout the clusters. Furthermore, we
show enrichment in the typical conservation patterns and
other miRNA-like properties in the vicinity of known miRNA genes,
compared with random genomic regions. This may imply
that additional, yet unknown, miRNAs reside in these
regions, consistent with the current recognition that there are overlooked
miRNAs. Indeed, by comparing our predictions with cloning results and with
identified miRNA genes in other mammals, we corroborate the predictions
of 18 additional human miRNA genes in the vicinity of
the previously known ones. Our study raises the
proportion of clustered human miRNAs that are <3000 nt apart to 42%.
This suggests that the clustering of miRNA genes is higher than
currently acknowledged, alluding to its evolutionary
and functional implications.Altuvia Y, Landgraf P, Lithwick G, Elefant N, Pfeffer S, Aravin A, Brownstein MJ, Tuschl T, Margalit H. Department of Molecular Genetics and Biotechnology, Faculty of Medicine, The Hebrew University PO Box 12272, Jerusalem 91120, Israel. Nucleic Acids Res. 2005 May 12;33(8): 2697-2706 |