Biology Reference
In-Depth Information
miRNAs (
Asirvatham
et al
., 2008
). Interestingly, miRNAs preferentially target
transcripts encoding transcription factors and the upstream signaling proteins
that activate them, while mRNAs encoding cellular receptors and ligands have
substantially fewer miRNA binding sites. Certain transcription factors play
indispensable roles in determining cell fate during hematopoiesis by acting as
“master regulators” of gene expression programs. Thus, their modulation by
miRNAs is consistent with the impact that miRNAs have been shown
genetically to have on cellular lineage choices during development.
The importance of precise levels of gene expression during hematopoiesis
(both for transcription factors and other regulatory proteins) has been clearly
demonstrated in recent years. Many papers have described distinct hemato-
poietic phenotypes in mice lacking only one of the two protein-coding alleles
at a particular locus (
Chan
et al
., 2011
;
Dahl
et al
., 2003
;
Egle
et al
., 2004
;
Eischen
et al
., 2004
;
He, 2010
;
Joslin
et al
., 2007
;
Kamimura
et al
., 2007
;
Kinjyo
et al
., 2002
;
Le Toriellec
et al
., 2008
;
Puebla-Osorio
et al
., 2011
;
Schraml
et al
.,
2008
;
Sernandez
et al
., 2008
;
Sportoletti
et al
., 2008
;
Sun and Downing, 2004
;
Wang
et al
., 2010
;
Xiang
et al
., 2010
;
Xiao
et al
., 2007
;
Zandi
et al
., 2008
)
(
Table 6.1
). A 50% reduction in expression of some genes can impact cell
lineage decisions, as has been elegantly demonstrated for PU.1 (
Dahl
et al
.,
2003
). At this locus, loss of a single allele triggers a skewing of the output of
granulocytes compared to monocytes. Subtle changes in gene dosage can also
impact cancer development, as in the cases of Pten, p53, and cMyc (
He, 2010
;
Salmena
et al
., 2008
), and this can precede or even be distinct from phenotypes
caused by loss of heterozygosity. Another example is Socs1, where heterozy-
gous mice display enhanced inflammatory responses to endotoxin (
Kinjyo
et al
., 2002
). The twofold effect of heterozygosity in mice is quantitatively
similar to the degree of protein expression changemediated bymanymiRNAs.
Thus, it is reasonable that loci displaying haploinsufficient phenotypes are often
ones that have functional miRNA binding sites within their 3
0
UTRs because
they should be genes that are susceptible to small, quantitative alterations.
Changes in gene expression dosage can also come about through aneu-
ploidy. One clear example of this is trisomy 21 which causes Down's
syndrome. The extra copy of chromosome 21 leads to elevated levels of
the genes it carries (
Arron
et al
., 2006
). This triggers many phenotypes
including an increased likelihood of developing acute leukemia. Thus, it is
clear that many lineage-determining signaling proteins and transcription
factors must be expressed at accurate levels to ensure proper hematopoietic
development, and miRNAs have likely evolved to meet such demands.
2.3. Combinatorial gene regulation by miRNAs
Most miRNAs have a broad repertoire of predicted mRNA targets. How-
ever, the number of targets involved in a specific miRNA-dependent
phenotype appears to vary. There have been many examples of miRNAs
