Biomedical Engineering Reference
In-Depth Information
Fig. 3.1
miRNA-target
recognition site types. The
four canonical site types are
shown for myotubularin
related protein 3 mRNA
3
UTR and human mir-16-1
prioritising candidates for wet-lab confirmation (Orom and Lund
2010
). This section
aims to give the reader an overview of the sequence-based rules that underpin the
most widely used target prediction algorithms from comparative sequence analyses
to thermodynamics.
3.2.1
MicroRNA Seed Region Base Pairing
Determining the degree of complementarity between bases 2-7 at the 5
end of the
mature miRNA sequence (termed the seed region) to the target transcript (some al-
gorithms require perfect Watson-Crick base pairing to the seed region) is the most
widely used feature in computational target prediction (Bartel
2009
). The importance
of this region was first highlighted by Lewis and co-workers who demonstrated a
greater degree of seed region conservation across several species than would be ex-
pected by chance (Lewis et al.
2003
). Furthermore, studies that perturbed specific
miRNAs followed by global expression profiling of mRNA (Lim et al.
2005
) and
proteins (Baek et al.
2008
; Selbach et al.
2008
) observed enrichment of seed region
target sites within the resulting differentially expressed gene/protein sets. It has also
been shown that mutations within the miRNA seed region can lead to an elimina-
tion of miRNA function, enhance or reduce their biogenesis (Sun et al.
2009
) and
result in the onset of disease (Hughes et al.
2011
; Mencia et al.
2009
). The extent
of gene expression repression is thought to be affected by variations in the num-
ber of contiguous bases and sequence composition of the gene target binding the
seed (Fig.
3.1
). It also should be noted that, in some instances, miRNA mediated
repression can occur in the absence of a seed region match. These “seedless” highly
complementarity miRNA-mRNA interactions have also been shown to mediate
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