Biology Reference
In-Depth Information
A hallmark of hematopoiesis is the uncoupled processes of cellular
differentiation followed by expansion of the newly formed cell type. This
process is continued until terminal differentiation is reached. Such a
dynamic process involves the expression of stage-specific genes, including
both mRNAs and miRNAs ( Kuchen et al ., 2010 ). Based upon these
features, one can imagine that at proliferative stages where synthesis of a
particular miRNA ceases, cell division and subsequent growth will lead to
effective dilution of the miRNA as a mechanism of reducing its concentra-
tion. When developing cell populations exit the cell cycle and begin to
further differentiate, the miRNAs they produce will be able to efficiently
increase in concentration within the quiescent cell. Thus, such a dynamic
system can make use of its various cell states to regulate miRNA abundance
and therefore gene expression even though the miRNAs themselves may be
intrinsically quite stable.
3.3. Regulating miRNA interactions with mRNA 3 0 UTRs
While many mRNA targets can be predicted for a given miRNA based
upon the presence of conserved 3 0 UTR sites coupled with thermodynamic
considerations, it is common to observe only a fraction of predicted target
mRNAs being repressed in response to their cognate miRNA within a
given cell type. Obviously, an important prerequisite of miRNA targeting
of an mRNA is concurrent spatial and temporal expression of both mole-
cules. However, this does not seem a sufficient explanation of why certain
targets are not repressed. Thus, additional levels of regulation must exist.
Current studies have begun to expand our understanding of why coex-
pression of a miRNA and its target mRNA is not always sufficient to trigger
repression. One explanation is a loss of the miRNA binding site by the
target mRNA under certain conditions. For instance, when T lymphocytes
proliferate following their activation, they have been shown to express
mRNAs with shortened 3 0 UTRs as a result of usage of alternative poly-
adenylation sites ( Sandberg et al ., 2008 ). This site shift can result in a loss of
miRNA binding sites, rendering these transcripts unresponsive to miRNA-
mediated repression. To date, the consequences of this transcript shortening
are still under investigation.
On the other hand, some miRNA-targeted mRNAs can undergo
alternative splicing and lose terminal exons and adjacent downstream
miRNA binding sites in the process. This has been shown for some targets
of miR-155, which is a major regulator of hematopoietic development and
function ( Xu et al ., 2010 ). Yet another regulatory mechanism involves
RNA-binding proteins, including Dnd1 and Elavl1, which have the poten-
tial to interact with specific 3 0 UTRs and guard them against or promote
miRNA-mediated repression ( Kedde et al ., 2007 ; Kim et al ., 2009 ).
mRNAs have also been shown to undergo compartmentalization within
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