Biology Reference
In-Depth Information
3. Controlling MicroRNA-Mediated
Repression of mRNA Targets
In recent years, much has been learned about the mechanistic basis of
miRNA biogenesis and subsequent target repression, and this has been
reviewed exhaustively elsewhere (
Filipowicz
et al
., 2008
). It has become
very clear that this is an extensively regulated process that is controlled by a
variety of different molecular mechanisms at different steps during the
biogenesis process (
Fig. 6.1
). In this section, many of these points of
regulation will be discussed including ways in which the highly dynamic
hematopoietic system benefits through control by miRNA levels.
3.1. MicroRNA biogenesis and function
miRNAs are transcribed most commonly by RNA polymerase II, and this
process is therefore regulated by the armamentarium of transcription factors
available in any one cell type. Thus, like the protein-coding genes of specific
cells, miRNAs are first controlled at the level of transcription and can be
part of the suite of genes regulated by master regulators to help confer
cellular identity. After the primary miRNA transcript is produced, it begins
being processed into a pre-miRNA by the enzymes Drosha and DGCR8
(
Filipowicz
et al
., 2008
). In addition, other factors such as KSRP, which are
expressed in blood cells, also bind to the loop region of the primary
transcript and further manage processing of the nascent RNA molecule
Genome
Transcription
Deamination
Processing
Nuclear export
Uridylation
Strand selection
Mature
miRNA
Stoichiometry
Subcellular localization
Turnover
Differential polyA sites
mRNA splicing
RNA BPs
3
¢
UTR
binding
3
¢
5
¢
CDS
“seed”
Figure 6.1
The regulation of miRNA function—miRNAs are first controlled by
transcription which gives rise to a primary transcript. Following a number of indicated
regulatory events, the mature miRNA is loaded into the RISC complex. There are also
distinct regulatory steps that control miRNA-RISC complex interactions with target
mRNAs.
