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Cantone Reversal of X chromosome inactivation

Table 1: Differences between mouse and human X chromosome inactivation
Mouse Human
Random XCI initiation Late blastocyst Unknown
X chromosome dampening Not detected Dosage compensation mechanism (pre-implantation)
Imprinted XCI (embryonic) Xp inactivation (4-cell stage) /reverted in epiblast Not detected
(mid-blastocyst stage)
Imprinted XCI (extra-embryonic) Xp inactivation (mantained in trophoectoderm) Not detected
XIST expression and localization Mono-allelic Xi expression and coating upon Bi-allelic expression and XaXa coating ahead of
random XCI random XCI
Tsix/TSIX expression and function Xa expression; Xist antagonist No expression (pre-implantation)/ Xi expression (foetal
cells); unknown function
XACT expression and function No orthologue identified XaXa expression and coating ahead of random XCI;
XIST antagonist?
XCI: X chromosome inactivation; Xi: inactive X chromosome; Xp: paternal X chromosome; Xa: active X chromosome

be used to segregate different pluripotent states with This information might help us to achieve locus-
distinct X chromosome epigenetic features in single cells, specific control of Xi reactivation and to engineer novel
as it can induce the expression of genes associated with therapeutic strategies for X-linked diseases that will be
both the primed and naïve human pluripotent states [129] . based on the re-expression of the silent allele from the
This information might be useful for identifying pathways Xi. Furthermore, these studies will give us mechanistic
that stabilize naïve pluripotency and for refining culture insights into human diseases in which the reactivation
conditions. of genes along the Xi has been observed, including
cancer [135-137] , age-related [138,139] and autoimmune
The controversies regarding XCI state in human diseases [140] .
pluripotent cells also highlight the importance of
standardized protocols for determining XCI status. DECLARATIONS
Indirect measurements of XCI, such as the presence of
XIST nuclear foci and/or the expression ratio between
X and autosomes, as well as analyses of few X-linked Authors’ contributions
I. Cantone contributed solely to the paper.
genes with only one methodology (e.g. RNA-FISH
or allele-specific RT-PCR) might be misleading [57] .
The advent of genome-wide techniques that can be Financial support and sponsorship
None.
used to assess allele-specific expression at the single
cell level will be fundamental in defining different XCI Conflicts of interest
states and investigating the susceptibility of distinct There are no conflicts of interest.
Xi loci to reactivation. In addition, it will be important
to reach an agreement about whether Xi expression Patient consent
should be defined as percentage of expression Not applicable.
relative to the Xa or based on more sophisticated
statistical methods [129,132-134] . Notably, the combination Ethics approval
of molecular and cell biology techniques applied to Not applicable.
human pluripotent cells before and after differentiation
is required to distinguish naïve from primed and
eroded pluripotency. Finally, another important aspect REFERENCES
to consider is the variability of XCI in different tissues
and individuals [10] . This variable Xi expression will 1. Lyon MF. Gene action in the X-chromosome of the mouse (Mus
need to be taken into account, and studies of XCI in musculus L.). Nature 1961;190:372-3.
a large number of subjects and in different tissues 2. Deng X, Berletch JB, Nguyen DK, Disteche CM. X chromosome
will be required to achieve a better understanding of regulation: diverse patterns in development, tissues and disease. Nat
how cellular context influence locus susceptibility to Rev Genet 2014;15:367-78.
reactivation. 3. Schmidt M, Du Sart D. Functional disomies of the X chromosome
influence the cell selection and hence the X inactivation pattern in
In perspective, studies of human pluripotent females with balanced X-autosome translocations: a review of 122
cases. Am J Med Genet 1992;42:161-9.
reprogramming will allow us to dissect the precise 4. Peeters SB, Yang C, Brown CJ. Have humans lost control: the elusive
molecular mechanisms of Xi reactivation and to X-controlling element. Semin Cell Dev Biol 2016;56:71-7.
unravel locus-specific susceptibilities to reactivation. 5. Dobyns WB, Filauro A, Tomson BN, Chan AS, Ho AW, Ting
10 Journal of Translational Genetics and Genomics ¦ Volume 1 ¦ November 16, 2017