Page 36 - Read Online

Cerase. J Transl Genet Genom 2018;2:3 Journal of Translational
DOI: 10.20517/jtgg.2018.02 Genetics and Genomics

Editorial Open Access

Awakening the sleeping giant: methods for
reactivating the inactive X chromosome as clinical

treatment for X-linked disorders

Andrea Cerase

European Molecular Biology Laboratory, Monterotondo 00015, Italy.
Correspondence to: Dr. Andrea Cerase, European Molecular Biology Laboratory, Via Ramarini 32, Monterotondo 00015, Italy.
E-mail: andrea.cerase@embl.it
How to cite this article: Cerase A. Awakening the sleeping giant: methods for reactivating the inactive X chromosome as clinical
treatment for X-linked disorders. J Transl Genet Genom 2018;2:3.https://doi.org/10.20517/jtgg.2018.02

Received: 13 Jan 2018 First Decision: 18 Jan 2018 Revised: 21 Jan 2018 Accepted: 22 Jan 2018 Published: 1 Mar 2018
Science Editor: Jian-Min Chen Copy Editor: Jun-Yao Li Production Editor: Huan-Liang Wu

During evolution, the mammalian X chromosome acquired brain-related genes. Mutations of X-linked genes
account for up to 30% of intellectual disabilities, 20% of which are linked to autism spectrum disorders .
[1,2]
Epimutations on the X chromosome have also been associated with a number of mental health conditions (e.g.
depression, bipolar disorder and schizophrenia) . Thanks to X chromosome inactivation (XCI), a mechanism
[3-6]
which reversibly silences one of the two X chromosomes in females, female mammals are a somatic mosaic
of two populations of cells, expressing either the paternal or the maternal X chromosome, usually in a 50-50
[7-9]
ratio . This aspect of female biology is particularly relevant for X-linked dominant disorders. Indeed, while
males die at birth or have very severe phenotypes from X-linked mutations, heterozygous female mammals
[10]
tolerate them, due to the presence of the wild type (WT) gene on the other X chromosome . Therefore, in
females, it is in principle possible to re-activate the WT XCI-silenced copy of the gene in order to alleviate or
rescue any given disease phenotype. This is critical for a variety of genetic pathologies, ranging from poorly
characterized genetic diseases such as CDKL5 syndrome to more frequent and better-described diseases, such
as Rett syndrome.

In this special issue, Cantone describes the reversal of XCI during development and reprogramming by
[11]
expression of pluripotency factors, cell fusion or somatic cell nuclear transfer. Cantone also compares and
[11]
[12]
contrasts human and mouse systems, emphasising significant differences between them. Przanowski et al.
discuss pharmacological and genetic ways to reactivate the inactive X chromosome (Xi). They summarise the
efforts that have been made to date to achieve Xi reactivation using these approaches alone or in combination.
The authors also compare various experimental cellular systems, highlighting the benefits and limitations of

© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

www.jtggjournal.com