Biology Reference
In-Depth Information
as well as repress a key epigenetic component of the PRC2 complex, Suz12,
which together with PRC1 functions in epigenetic silencing of genes
through H3K27me3 trimethylation (
Iliopoulos
et al
., 2010
).
Together, these findings provide critical mechanisms that link miRs to
cancer stem cells. Recently, a chemical screen specifically targeting breast
cancer stem cells led to the identification of compounds that are particular
effective to reduce the cancer stem cell population (
Gupta
et al
., 2009
).
With the emerging roles of miRs in cancer stem cells, it is tempting to
speculate that studies specifically focusing on miRs in these often rare cell
populations could yield novel insights toward diagnosis and treatment in the
future.
14. Closing Remarks and Future Challenges
Functional characterization of miRs in mammalian development and
adult stem cells is still in its infancy. Much of our knowledge of the just how
critical miRs are to mammalian development can still be traced to the global
miR depletion studies in which
Dicer
and
Dgcr8
were ablated specifically in
either embryonic stem cells or adult tissues. The strong defects in differen-
tiation and minor defects in proliferation appear to be a recurring theme,
whether for embryonic or adult SCs (
Kanellopoulou
et al
., 2005; Murchison
et al
., 2005; Wang
et al
., 2007
). However, ESCs and adult tissues do show
some notable differences, for instance, those showing that the differences
between
Dicer
- and
Dgcr8-
deficient ESCs and mouse oocytes are signifi-
cantly greater than for skin lineages (
Suh
et al
., 2010; Wang
et al
., 2007
).
That said, it is notable that endo-siRNAs, accounting for much of the
difference between
Dicer
and
Dgcr8
null phenotypes, have only been
detected in ESCs and oocytes and not in adult tissues in mammals
(
Babiarz
et al
., 2011; Suh
et al
., 2010; Tam
et al
., 2008; Watanabe
et al
.,
2008
). In this regard, it is also interesting to note that lin-28, a key
downstream target of lin-4 in
C. elegans
, is also primarily restricted to
mammalian ESCs and is generally not seen in adult SCs. Whether these
differences are reflective of the unique pluripotent state of the ESCs remains
to be addressed in the future.
Among the myriad of key issues that remain unresolved is the question
regarding the role of a single miR or miR family in the regulation of
mammalian development and stem cells. When
C. elegans
miRs are
knocked out individually or by the whole family that share the same seed
sequences combinatorially, only a few exhibit developmental defects
(
Alvarez-Saavedra and Horvitz, 2010; Miska
et al
., 2007
). Similarly, with
more than 30 miRs having been individually knocked out to date without
affecting viability in mice, it is evident that the loss of a single miR or even a
