Biomedical Engineering Reference
In-Depth Information
Fig. 2.1
Overview of mammalian miRNA biogenesis and function. The primary (pri-) miRNA
transcripts that can adopt hairpin-like structures are transcribed from miRNA loci. Pri-miRNA
transcripts from miRNA genes are processed to 60-80 nt pre-miRNA transcripts by a complex
containing Drosha and DGCR8 in the nucleus. Alternatively, pre-miRNA may be derived from
intronic regions of protein-coding genes in a Drosha/DGCR8 independent process requiring both
the splicesome and a debranching enzyme known as the lariat debranching enzyme. Both the canon-
ical Drosha-dependent processing and intronic processing pathways generate a pre-miRNA with a
hairpin-like structure that is then exported out of the nucleus into the cytoplasm through Exportin 5
(EXP5). Along with Argonaute (Ago) proteins, Dicer processes the pre-miRNA transcript into a ma-
ture miRNA duplex. The strand in the duplex with the least thermodynamically stable 5
end (guide
strand) is retained by an Ago protein in mammals. The passenger strand (miRNA
∗
) is generally
released and degraded. Upon target recognition by the RNA-induced silencing complex (RISC)
based on the seed region complementarity with the target mRNA, the target mRNA undergoes
translational repression
receptor liver X receptor-alpha (LXR
) (Ou et al.
2011
). The sterol response ele-
ment binding protein (SREBP), a target of LXR
α
, binds an SREBP response element
in the promoter of hsa-miR-613 and enhances its expression, thus down-regulating
the expression of LXR
α
(Ou et al.
2011
). Similarly, the expression of the clustered
miRNA hsa-miR-2861 and hsa-miR-3960 is regulated by runt-related transcription
factor 2 (Runx2), a key transcription factor that promotes osteoblast differentia-
tion (Hu et al.
2011
). Runx2 enhances the transcription of hsa-miR-2861 which
results in the repression of histone-deacetylase 5 thereby inhibiting the repression
of Runx2 to further promote osteoblast differentitation (Li et al.
2009
). Runx2 also
enhances the expression of hsa-miR-3960. A target of hsa-miR-3960 is homeobox
a2 (Hoxa2), a protein that suppresses Runx2 expression (Hu et al.
2011
). Thus, the
α
Search WWH ::
Custom Search