Biology Reference
In-Depth Information
indefinitely in a suitable environment enabling pluripotency to be main-
tained. The pluripotent state of ESCs is sustained by a core network of
transcription factors and by chromatin remodeling factors that perpetuate
an environment that is permissive for transcription (reviewed in
Boyer,
Mathur, & Jaenisch, 2006; Cole & Young, 2008; Niwa, 2007
). Although
we do not yet know how these core transcription factors and chromatin
remodelers act in preserving pluripotency during stem cell self-renewal,
the presence of “bivalent” chromatin at the promoters of lineage-specific
genes has been implicated in establishing a chromatin context in which mul-
tiple lineage options are primed in readiness for subsequent developmental
cues (reviewed in
Spivakov & Fisher, 2007
). This bivalent chromatin is
characterized by being marked with opposing histone modifications that
correlate with both “repressive” and “active” gene expression. ESCs grown
in the presence of differentiation inhibitors (so-called 2i;
Ying et al., 2008
)
show a reduction in bivalent marking (
Marks et al., 2012
) and are pluripotent
but are less prone to differentiation.
Under specific conditions, differentiated cells can reset their lineage affil-
iation and revert to a multi- or pluripotent state. This was first shown
in amphibians by transferring nuclei of late stage embryos into enucleated
oocytes (
Briggs & King, 1952; Gurdon, 1962; Gurdon, Laskey, &
Reeves, 1975; King & Briggs, 1955
). More recently, the isolation of
so-called iPSCs (induced Pluripotent Stem Cells) by the forced expression
of four pluripotency-associated factors has independently confirmed that
terminally differentiated cells can reassume pluripotency (
Takahashi &
Yamanaka, 2006
; reviewed in
Stadtfeld & Hochedlinger, 2010
). This has
raised expectations that patient-specific pluripotent stem cells could be
“tailor made” for cell replacement therapy and catalyzed scientific efforts
to understand the molecular mechanisms of reprogramming as well as those
that underwrite ESC proliferation.
One of the most remarkable features of ESCs is their rapid cell division.
Fast cell division is accomplished by a selective reduction in the Gap (G)
phases of the cell cycle (G1 and G2 phase) rather than by shortening
DNA Synthesis (S) phase or mitosis (
Becker et al., 2006; Fluckiger
et al., 2006; Neganova, Zhang, Atkinson, & Lako, 2009; White &
Dalton, 2005
). Here, we review some recent data describing the unusual
features of ES cell cycle and outline the proposal that an altered cell-
cycle structure may be critical
in determining successful pluripotent
reprogramming.
