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Page 12 of 15 Przanowski et al. J Transl Genet Genom 2018;2:2 I http://dx.doi.org/10.20517/jtgg.2017.03

open questions remain. How many XCI activators and repressors exist? How do these regulators function
in different stages of XCI, and are they cell-type or cell-stage specific? These and many other questions
remain to be addressed. But as futurists predicted, we are in a state of active technological revolution;
this advancement has provided us with powerful tools to interrogate the mechanism of XCI much more
intricately than what was possible only a few years ago. Recent studies have identified several regulatory
elements that are required for the initiation, establishment, and maintenance of XCI. Such studies have also
revealed the plasticity of the inactive state of the X chromosome, which was previously limited to early stages
of embryogenesis or induced pluripotency.

As discussed earlier, new tools have been developed recently that have aided our understanding of XCI,
especially by identifying proteins that either interact with Xist or transcriptionally regulate its expression.
Using elegant tools, the structural and organizational maps of Xi in the nucleus have also been generated. In
light of recent findings, we now realize that XCI is more variable than previously thought, and that its outcome
is dependent on the crosstalk of different regulatory elements at multiple levels. Diverse molecular, biochemical,
and genetic approaches have identified more than 500 proteins that are involved in XCI [Figure 2], with 87 of
them having been validated using a single-gene approach [Table 1]. How these different proteins regulate the
silencing of XCI, or which steps of XCI are regulated by these factors, remains to be addressed. However, the
emerging fact from these studies does point to multiple gene-silencing mechanisms. Pathway analysis [72,73]
revealed that newly discovered XCIFs can be categorized into 14 different pathways, that include: Wnt
signaling pathway, p53 pathway, TGF-β signaling pathway, p53 pathway feedback loops 2, and EGF receptor
signaling pathway [Figure 3].

Finally, an important therapeutically relevant question is, can Xi be reactivated to compensate for gene
deficiencies in X-linked diseases? One such example is Rett syndrome, which is a rare neurodevelopmental
disease caused by loss-of-function mutations in the X-linked gene MECP2 encoding Methyl CpG binding
protein. As discussed above, reactivating Xi-linked MECP2 in Rett syndrome patients can restore symptoms
associated with the disease and possibly reverse the disease [74-76] . But the lack of understanding of XCI has
limited its applicability as a target for treatment. The identification of molecular players in XCI could be
beneficial in expediting efforts to develop XCR-based therapeutic approaches. In fact, many of the XCIFs
identified are druggable and efforts are underway to target them for pharmacological interventions.

DECLARATIONS
Authors’ contributions
All authors contributed to the paper writing.

Financial support and sponsorship
None.

Conflicts of interest
There are no conflicts of interest.

Patient consent
Not applicable.

Ethics approval
Not applicable.

Copyright
© The Author(s) 2018.