Nuclear reprogramming and epigenetic rejuvenation.
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Date
2010-06
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Abstract
William Harvey’s motto Ex ovo omnia (‘All from the egg’)
on the frontispiece of his treatise On the generation of
living creatures (1651) was well chosen and extraordinarily
prescient. Centuries later, the egg was shown to have a striking
capacity for bringing forth life – life produced by experimental
manipulation, ‘animal cloning’, outside the normal physiology
of fertilization (Gurdon and Byrne 2005). Cloning through
somatic cell nuclear transfer (SCNT) showed that the restriction
of developmental potential during cellular differentiation is
the result of epigenetic changes in gene expression rather
than through loss of DNA – although certain lineages, such
as B- and T-cells, are known to undergo programmed DNA
rearrangements (Hochedlinger and Jaenisch 2002). It is the
reversal of these epigenetic changes during ‘reprogramming’
of the specialized adult nucleus within the reconstructed
embryo that results in its re-acquisition of developmental
potential and the consequent recapitulation of development,
ultimately giving rise to a cloned newborn.
A commonly held defi nition is that nuclear reprogramming
by SCNT is the process by which a specialized nucleus reacquires
developmental potential (Singh 1999). However,
nuclear reprogramming is much more than this. It is a manylayered
process. Intimately associated with developmental
reprogramming of the specialized adult nucleus to an
earlier, embryonic, totipotent state is age reprogramming;
the ageing ‘clock’ of the transferred nucleus is reset
back to zero; an old cell can give rise to newborn clone
(Wilmut et al. 1997). This begs the question of whether
age reprogramming can be separated from developmental
reprogramming. Being able to reprogramme the ageing
clock in isolation, while maintaining the differentiated state
of a cell, would essentially mean that the cell is made young
again: rejuvenated. Clearly, should this be achieved, the
consequences would be profound (fi gure 1). Nuclear reprogramming observed in ‘classical’ animal
cloning (where adult cells are reprogrammed to an embryonic
state after SCNT) has recently been recapitulated in vitro by
the generation of embryonic-like induced pluripotent stem
cells (iPS cells; Takashi and Yamanaka 2006). Induction
of iPS cells allows the process of epigenetic rejuvenation
of adult cells to embryonic cells, as seen after SCNT, to
be studied in a well-defi ned system (Surani and McClaren
2006). However, certain features of the rejuvenation seen in
classical cloning are likely to differ from that seen in iPS
cell generation. For one, telomeres, whose shortening is
seen as a key characteristic of ageing cells, are ‘rejuvenated’
by telomerase during iPS cell induction from old somatic
cells (Marion et al. 2009). This mechanism is unlikely to be
the major mechanism for ‘rejuvenating’ telomeres in eggs
after SCNT. During the early cleavage divisions, telomeres
are lengthened by a telomere sister-chromatid exchange
recombination mechanism that is peculiar to this stage of
development and is under the sole control of the maternal
cytoplasm, as it is unaffected by the absence of a paternal
chromosomal complement (Liu et al. 2009). Thus, the
mechanism(s) and pathway(s) of rejuvenation that result
from SCNT, which have yet to be uncovered, are likely
to be different from those operating during the generation
of iPS cells. Notwithstanding these differences, SCNT or
introduction of ‘reprogramming factors’ into somatic cells
both appear to direct developmental reprogramming and
age reprogramming seamlessly: age reprogramming does
not take place without de-differentiation into embryonic
cells (developmental reprogramming). But can these
intimately associated aspects of nuclear reprogramming be
disentangled? While it seems hardly possible, recent work
indicates that age reprogramming might indeed be separable
from developmental reprogramming.
Differentiation of myelomonocytic progenitors
into macrophages involves an exit from the cell cycle.
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Keywords
Epigenetics, iPS cells, rejuvenation, reprogramming, SCNT
Citation
Singh Prim B, Zacouto Fred. Nuclear reprogramming and epigenetic rejuvenation. Journal of Biosciences. 2010 Jun; 35(2): 315-319.