Biology Reference
In-Depth Information
Most of the genome is transcribed. However, only about 1.5% of
transcripts encode proteins; the vast majority of cellular RNAs are noncod-
ing (
Mattick, 2007
). In recent years, much progress has been made in our
understanding of certain classes of noncoding RNAs, including the miR-
NAs, piwi interacting RNAs, small nucleolar RNAs, long intergenic non-
coding RNAs, and RNA transcripts antisense to coding genes (
Bartel and
Chen, 2004
;
Guttman
et al
., 2009
;
Khanna and Stamm, 2010
;
Khurana and
Theurkauf, 2010
;
Malecova and Morris, 2010
). Many of these RNA species
are evolutionarily conserved in sequence, exhibit tissue-specific expression
patterns, and are involved in modulating specific cellular pathways and
functions. Here, we will focus primarily on the miRNAs.
miRNAs play critical regulatory roles at many stages of hematopoiesis,
ranging from stem cells to terminal differentiation. We begin with a discus-
sion of why miRNAs may have evolved to regulate developmental pro-
cesses like hematopoiesis. The types of regulatory strategies used by
miRNAs and the pathways that regulate miRNA function are then dis-
cussed, followed by an analysis of how miRNAs have emerged to impact
distinct stages of hematopoiesis. Finally, the relevance of miRNAs to
hematopoietic diseases that stem from developmental mishaps, as well as
translational applications, is addressed. More complete catalogs of specific
studies on these topics are presented elsewhere (
Lodish
et al
., 2008
;
O'Connell
et al
., 2010c
;
Xiao and Rajewsky, 2009
); this discussion is
intended to be more of a conceptual overview.
2. The Emerging Importance of MicroRNAs
During Hematopoietic Development
2.1. MicroRNAs and the stabilization of complex phenotypes
As more genomes have been fully sequenced, it has become clear that
increased organismal complexity is primarily driven by new forms of
gene regulation and not gene number. Aside from the primary event of
transcriptional regulation, relevant activities include posttranscriptional
mechanisms like alternative splicing or polyadenylation, which can generate
many protein derivatives from a single gene. Other types of posttranscrip-
tional regulation include modifications of transcript stability, which are
regulated in part by miRNAs. Following their biogenesis, miRNAs enter
the cytoplasmic RNA-induced silencing complex (RISC) which helps
guide them to interact with mRNA 3
0
UTRs through the agency of specific
base pairing (
Filipowicz
et al
., 2008
). This, in turn, triggers reduction of
target mRNA levels and protein output, although other mechanisms
of action may be relevant. Because there are many hundreds of different
miRNAs
in humans—with many predicted to target hundreds of
