Mitosis to behave as mitotic bookmarking factors has

Mitosis constitutes the most dramatic reorganisation of the nucleus and
the chromatin experienced during the life of a cell (de Castro et al., 2016;
Hirano, 2015). Hence, mitosis has long been considered to be refractory for
transcriptional regulation (Fig. 2). Despite this, longstanding results have
shown that cells in metaphase are more sensitive to DNA denaturation than in
interphase (Darzynkiewicz et al., 1977a, b), an observation that was later
substantiated by the detection of increased levels of single-strand DNA in
mitotic chromosomes (Juan et al., 1996). These features were directly related
to gene regulation: promoters active in interphase were shown to display DNA
unwinding in mitosis (Gazit et al., 1982; Martinez-Balbas et al., 1995) and
displayed evidence of transcription factor binding (Michelotti et al., 1997).
These early studies, which may be considered as the birth of the field of
mitotic bookmarking (Michelotti et al., 1997), suggested that the propagation
of an open chromatin structure associated with transcription factor binding may
facilitate the prompt reactivation of transcription in interphase (Fig. 2). In
the following decades, the number of transcriptional regulators that have been
suggested to behave as mitotic bookmarking factors has progressively increased
(Table 1). Most of the proteins initially reported as binding mitotic chromatin
were general transcription factors and ubiquitous regulators of transcription
and chromatin, such as TBP, Brd4 and p300. Subsequently, the recognition that
some sequence-specific developmental transcription factors, such as Runx2
(Young et al., 2007), Gata1 (Kadauke et al., 2012) and FoxA1 (Caravaca et al.,
2013), can also bind to mitotic chromatin, opened a new avenue to understand
how transcription factors both establish and contribute to the maintenance of
cell type-specific transcription profiles in dividing cells. To date, the field
of mitotic bookmarking is currently focused on three broad and interrelated
areas. The first aims to understand, at the molecular level, how
transcriptional regulators bind mitotic chromatin and whether they functionally
interact with specific activities driving mitosis. This is important because
depending on how gene regulators bind with mitotic chromatin, different
molecular and biological consequences are to be expected. The second aim is
more functional, since it remains unknown whether, and by what mechanism,
bookmarking factors accelerate gene reactivation following mitosis. Since
mitotic bookmarking factors are not persistently bound to the chromatin during
mitosis but rather exhibit a hyper-dynamic behaviour, it is not clear how they
provide an advantage to their mitotic targets. Finally, the third and perhaps
most conceptually challenging area of research is whether mitotic bookmarking
confers a memory of gene regulation. If proven, then it would clearly provide a
fresh conceptual framework for not only developmental biology, but also areas
of biology where cell proliferation and transcription factors play a
predominant role.


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