Awakening the sleeping giant: methods for reactivating the inactive X chromosome as clinical treatment for X-linked disorders

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)^[3-6]. Thanks to X chromosome inactivation (XCI), a mechanism 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 ratio^[7-9]. 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 tolerate them, due to the presence of the wild type (WT) gene on the other X chromosome^[10]. 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^[11] describes the reversal of XCI during development and reprogramming by expression of pluripotency factors, cell fusion or somatic cell nuclear transfer. Cantone^[11] also compares and contrasts human and mouse systems, emphasising significant differences between them. Przanowski et al.^[12] 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 these reporter systems. Reviews from both teams are highly complementary and provide the reader with an accurate, comprehensive picture of the progress made so far in this field.

Partial reactivation of the inactive X chromosome for therapeutic approaches has so far proven hard to achieve and control. Nevertheless, it offers a new and exciting perspective for curing X-linked disorders. Most importantly, I believe that the knowledge gained by studying the reversal of the Xi goes well beyond X inactivation. Similar strategies could be used for treating a broad range of common illnesses, such as mental health disorders linked to epigenetic gene-silencing, and some forms of cancer.