Novel molecular players of X chromosome inactivation: new technologies and new insights

Abstract

The dosage compensation in placental mammals is achieved by silencing of one copy of the X chromosomes in a female cell by a process called X chromosome inactivation (XCI). XCI ensures equal gene dosage for X-linked genes between the two genders. Although the choice of X chromosome to be silenced is random, once the silencing of the X chromosome has been established, this process is highly regulated and maintained throughout subsequent cell divisions. A long non-coding RNA, Xist , and its interacting proteins execute this multistep process, but several of these regulatory proteins remain unidentified. Recent technological advances based on the genetic and proteomics screening have identified several new regulatory factors as well as dissected the molecular details of XCI regulation. Moreover, identification of regulators of XCI offers an opportunity to explore reactivation of the inactive X chromosome (Xi ) as a potential therapeutic strategy to treat X-linked diseases, like Rett syndrome. Here, we summarize recent reports that identified new regulatory proteins and RNA species playing a crucial role in Xist localization and spreading, recruitment of silencing machinery to the Xi , Xist interaction with chromatin, and structural organization of the Xi in the nuclei.

Diverse developmental strategies of X chromosome dosage compensation in eutherian mammals

“…Xist RNA acts via recruiting proteins. To date 80 proteins are shown to interact directly or indirectly with Xist RNA and their functional role in XCI was confirmed using different methods (Przanowski et al, 2018). The proteins bind to Xist RNA in the regions of conservative microsatellite repeats denoted with Latin letters -from A to F. Some of the Xist-interacting proteins are discussed in this sub-section and listed in Table 1.…”

“…Xi in eutherian somatic tissues has a number of common features that appear to correspond to general fundamental mechanisms underlying XCI (Moindrot and Brockdorff 2016;Pinter 2016;Przanowski et al, 2018). At the cytological level, Xi is detected as a dense chromatin spot (called Barr body) in female interphase nuclei.…”

“…Xist RNA is a nuclear transcript being expressed exclusively on the inactivated X chromosome. After XCI initiation, Xist RNA spreads along the X chromosome due to its capacity to bind nuclear proteins, is maintained in Xi chromatin, represses gene transcription, and forms facultative heterochromatin and Xi chromosome territory (Moindrot and Brockdorff 2016;Pinter 2016;Przanowski et al, 2018). However, in somatic tissues, gene silencing and Xi chromatin can be maintained in the absence of Xist RNA.…”

“…BINDING TO XIST RNA DURING rXCI IN MICEAll references are given in the text and inPrzanowski et al, 2018. …”

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

“…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.…”