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Cantone Reversal of X chromosome inactivation

A

B

C

Figure 1: X chromosome state in mouse and human female embryos. (A) Schematic of early developmental stages; (B) in mouse embryos,
both X chromosomes are transcribed upon the zygote genome activation (ZGA) at 2-cell stage. Imprinted inactivation of the paternal X
chromosome then takes place at the 4-cell stage and is followed by reactivation in the epiblast that will give rise to the embryo proper. Upon
implantation, the epiblast undergoes random XCI whereas imprinted XCI is maintained in extraembryonic lineages. As depicted, mouse Xi
is characterized by the expression and coating of Xist, whereas the Xa expresses Tsix, a long non-coding RNA that antagonizes Xist and
functions specifically in mouse but not in human; (C) in human embryos, the two X chromosomes are transcribed upon ZGA at 4-cell stage
and remain transcriptionally active throughout pre-implantation development. XIST and another human-specific long non-coding RNA, XACT,
coat both active X chromosomes in human embryos. Notably, XIST RNA does not tightly localize on the X chromosomes but shows a diffuse
pattern and its coating is not accompanied by enrichment of H3K27me3. H3K27me3 enrichment is instead observed along the Xi upon XCI
initiation. XCI: X chromosome inactivation; Xi: inactive X chromosome; Xa: active X chromosome; PGC: primordial germ cell

to model Xi reactivation and unravel its molecular mouse and human cells, emphasize specie-specific
mechanisms. Reversal of X inactivation has, in differences and recent advances in reprogramming-
fact, been observed when mouse somatic cells are mediated human Xi reactivation.
reprogrammed towards a pluripotent state. A tight link
between pluripotency and reversal of XCI has been REPROGRAMMING-MEDIATED Xi
demonstrated [45-48] , and reprogramming of somatic REACTIVATION IN MOUSE
cells towards pluripotency has been widely used to
investigate its dynamics and molecular mechanisms
in mouse [49-52] . In human, the connection between In mouse embryos, the two X chromosomes undergo
[63,64]
pluripotency and Xi reactivation has instead been several rounds of inactivation and reactivation
controversial as different Xi states have been reported [Figure 1A and B]. The first round of XCI takes place
in human embryonic stem cells (ESCs) [53-57] and in at the 4-cell stage and leads to the inactivation of the
induced pluripotent stem cells (iPSCs) [55-59] . The lack of paternally-inherited X chromosome. This imprinted form
defined culture conditions that stabilize an embryonic- of XCI is followed by reactivation in the epiblast cells of
like pluripotent state and the resulting epigenetic the blastocyst where random XCI is later established
instability of human pluripotent cells contributed to around implantation. Imprinted XCI is instead maintained
the observed variability. Recent studies in human in extraembryonic lineages. Interestingly, reversal of
embryos and ESCs suggest substantial differences X inactivation has also been observed during mouse
in the mechanisms of XCI between human and development when pluripotency genes are re-expressed
mouse thus highlighting the need for model systems in primordial germ cells (PGCs) [65-67] . In addition,
that allow to directly investigate the human Xi and several mouse pluripotency factors have been shown to
its reactivation [57,60-62] . Here, I review studies of Xi inhibit XCI [45-48] thus suggesting an intimate connection
reactivation during pluripotent reprogramming of both between pluripotency and the presence of two active

Journal of Translational Genetics and Genomics ¦ Volume 1 ¦ November 16, 2017 3