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nucleosome templating, where the contribution of chromatin writers and
chromatin readers has been postulated to be critical in conveying mitotic
memory (reviewed in
Fisher & Brockdorff, 2012
). Many proteins involved
in DNA synthesis, such as DNA polymerases, PCNA, and RPA, and in epi-
genetic inheritance, such as DNA methyltransferase 1 and CAF-1, are
known to colocalize at “replication foci” formed during S phase
(
Rountree, Bachman, & Baylin, 2000; Shibahara & Stillman, 1999; Waga
& Stillman, 1998
). In addition, a recent report has shown that some enzymes
that modify histones (such as Trithorax and Polycomb) continue to associate
with their response elements during S phase (
Petruk et al., 2012
). The
authors argue that as the modified histones are lost during S phase, these
enzymes may be responsible for reestablishing this epigenetic information
on the newly assembled nucleosomes (
Petruk et al., 2012
). Taken together,
these studies suggest that S phase offers an unrivaled opportunity to reset or
reprogram gene expression profiles.
Consistent with this idea, Mechali and colleagues have reported that the
ability of differentiated nuclei to replicate in
Xenopus
egg extracts is
enhanced when a single prior mitosis is permitted (
Lemaitre, Danis,
Pasero, Vassetzky, & M´chali, 2005
). Moreover, preincubation of nuclei
with mitotic-phase
Xenopus
egg extracts increased the number of iPSCs
obtained using a conventional reprogramming factor cocktail (
Ganier
et al., 2011; Lemaitre et al., 2005
). The authors propose that the chromo-
some structure of an adult differentiated nucleus is not well adapted
for DNA replication and hence preconditioning is necessary for DNA
replication to be elicited (
Lemaitre et al., 2005
). Mitotic conditioning
may also allow increased recruitment of replication initiation factors onto
chromatin and a shortening of topoisomerase II-dependent chromatin
loops. Both these events might lead to the reduced inter-origin spacing that
characterize early developmental stages (
Walter & Newoirt, 2000; Wu, Yu,
& Gilbert, 1997
).
We have also seen that cell fusion-based pluripotent reprogramming is
more efficient using ESCs that are in S and G2 phases of the cell cycle
(
Tsubouchi et al., 2013
). These ESCs are capable of driving somatic nuclei
into precocious DNA synthesis in heterokaryons. Our studies revisit the
earlier work of Rao and Johnson (
Johnson & Rao, 1970; Rao &
Johnson, 1970
) in which Hela cells in S and G2/M phases of the cell cycle
were shown to induce premature DNA synthesis and chromosome conden-
sation upon fusion with G1 phase targets. The possibility that inducing
DNA synthesis facilitates successful reprogramming is also consistent with
