Biogenesis of Mammalian miRNA - MicroRNAs as Tools in Biopharmaceutical Production - page 16

2.1 Introduction

MicroRNAs (miRNAs) are small non-coding regulatory RNA molecules ( 22-nt)

that post-transcriptionally regulate gene expression by mechanisms involving trans-
lational repression and/or decreasing mRNA stability. For the purposes of this review,
the focus will be on regulation of mammalian miRNA biogenesis and mechanism
of action. Because an individual miRNA species can regulate many targets, and
because of the heterogeneity observed in mature miRNA sequences, miRNA serve
an essential role in controlling the expression of transcripts and proteins involved
in cellular development, differentiation, and metabolism. Furthermore, alterations
in either miRNA expression or the expression/activity of components required for
miRNA processing and target recognition may contribute to the pathogenesis of a
variety of cancers and other chronic diseases. Thus, characterizing the factors that
are responsible for controlling miRNA biogenesis is beneficial for enhancing our
understanding of mechanisms allowing cells to respond to constantly changing en-
vironmental conditions in addition to providing therapeutic opportunities to prevent
or treat chronic diseases.

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2.2 Principles of MicroRNA Biogenesis

miRNA-dependent regulation of gene expression is thought to control the expression
of as much as 60 % of the protein-coding genes expressed in mammals (Friedman
et al. 2009 ). miRNA represent about

1-2 % of the eukaryotic microtranscip-
tome and have diverse roles in modulating cellular processes including cellular
proliferation, differentiation, and metabolism in addition to being involved disease
pathogenesis (Liu et al. 2008 ; Williams 2008 ; Esau et al. 2006 ; Farazi et al. 2011 ).
miRNAs are transcribed primarily in an RNA polymerase II-dependent process
from intergenic regions of the genome or from introns and exons of protein-coding
genes (Fig. 2.1 ) (Kim and Nam 2006 ; Lee et al. 2004 ). The genomic organization
of miRNA genes is the subject of an excellent review article and will only be briefly
described here (Olena and Patton 2010 ). Approximately one-third of miRNA genes
are located in the introns of protein-coding genes suggesting that the expression of
miRNA and mRNA may be coordinately regulated (Westholm and Lai 2011 ; Ro-
driguez et al. 2004 ; Baskerville and Bartel 2005 ). In mammals

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36-46 % of known
miRNA are clustered as polycistronic genes (Griffiths-Jones et al. 2008 ). The ex-
pression of miRNA from these clusters suggests that multiple miRNAs affecting
multiple targets could be produced in response to environmental or developmental
cues. As an additional level of complexity, targets of polycistronic miRNA are often
regulated in such a way that multiple protein-protein interactions may be regulated by
the induction of miRNA expression and subsequent translational control (Yuan et al.
2009 ). Expression of miRNA transcripts may also play an important role in autoreg-
ulatory loops. For example, one of the targets of hsa-miR-613 is the nuclear hormone

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