Biomedical Engineering Reference
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Where it was shown that mature let-7 levels were very low in ES cells, pre-let-7
was quite abundant. Mechanistically, the presence of Lin-28 (also regulated by
core transcription factors) blocks the maturation of let-7. Thus, the fact that ES
cells are poised for efficient differentiation could be partly due to the presence of
precursor miRNAs, which can quickly become mature effector miRNAs upon
the onset of the differentiation program (e.g., let-7 g) (Viswanathan et al., 2008).
Apart from their collective roles in embryonic stem cell biology (miRNA
biogenesis-deficient ES cells), individual miRNAs have been shown to play a
role in lineage restriction, self-renewal, etc.
In our studies, we found a link between a transcription repressor (REST/
NRSF) and miRNA (miR-21) in the maintenance of self-renewal in mouse
embryonic stem cells (Singh et al., 2008). Although controversial at present,
with evidence in support and against it (Jorgenson et al., 2009, Buckley et al.,
2009, Singh et al., 2009), we found that REST blocks expression of miR-21
when cells are grown under self-renewal conditions. REST itself is quickly
down-regulated by proteasome-mediated degradation upon the onset of differ-
entiation (Ballas et al., 2005). This decrease in REST levels, in turn, leads to
increased expression of miR-21. The putative targets for miR-21, which are key
components of the network of transcription factors responsible for maintenance
of self-renewal in ES cells, include Sox2 and/or Nanog (Fig. 2). When over-
expressed in ES cells growing in the presence of LIF, miR-21 was able to down-
regulate self-renewal efficiency and the expression levels of various self-renewal
markers, including Sox2 and Nanog. The proposed model (see Singh et al., 2008)
is a reflection of how intricate networks of transcription factors and miRNAs
may co-operate to maintain self-renewal in ES cells (Singh et al., 2008). In
another example, when miR-134 (normally expressed in high levels in the adult
central nervous system) is overexpressed in ES cells it leads to its differentiation
toward ectodermal lineage and is able to block/overcome the signal from LIF in
the media. It was also shown that miR-134 is able to directly target Nanog and
LRH1 (Tay et al., 2008). One of the objectives of studying mES cells is to better
understand the underlying mechanisms of normal development and differentia-
tion. In vitro protocols now can guide the ES cells to differentiate into specific
lineages. In one such study, it was discovered that miR-133b (amid-brain-specific
miRNA) can negatively regulate the function of ES cell-derived dopaminergic
neurons by blocking Pitx3 and regulating dopamine synthesis (Kim et al., 2007).
4 The Role of miRNAs in Gene Expression
The role of transcription factors in the regulation of gene expression is well
established, and our understanding of how miRNAs regulate gene expression is
increasing. These two factors co-operate to establish a specific cell identity, and
they are remarkably similar at the mechanistic level (Hobert, 2008). Both
transcription factors and miRNAs have been shown to be pleiotropic and to
co-operate with different partners in a context-dependent manner; their
