Xist RNA and the Mechanism of X Chromosome Inactivation

Abstract

Dosage compensation in mammals is achieved by the transcriptional inactivation of one X chromosome in female cells. From the time X chromosome inactivation was initially described, it was clear that several mechanisms must be precisely integrated to achieve correct regulation of this complex process. X-inactivation appears to be triggered upon differentiation, suggesting its regulation by developmental cues. Whereas any number of X chromosomes greater than one is silenced, only one X chromosome remains active. Silencing on the inactive X chromosome coincides with the acquisition of a multitude of chromatin modifications, resulting in the formation of extraordinarily stable facultative heterochromatin that is faithfully propagated through subsequent cell divisions. The integration of all these processes requires a region of the X chromosome known as the X-inactivation center, which contains the Xist gene and its cis-regulatory elements. Xist encodes an RNA molecule that plays critical roles in the choice of which X chromosome remains active, and in the initial spread and establishment of silencing on the inactive X chromosome. We are now on the threshold of discovering the factors that regulate and interact with Xist to control X-inactivation, and closer to an understanding of the molecular mechanisms that underlie this complex process.

New meaning in the message: Noncoding RNAs and their role in retinal development

“…The twin nuclear-localized ncRNAs Xist and Tsix have been studied for a number of years now as critical regulators of X chromosome inactivation (Plath et al, 2002;Wutz and Gribnau, 2007). Xist and Tsix, both of which are mRNA-like and tens of kilobases long, are transcribed from the Xic (X-inactivation center) in antisense orientation and act antagonistically to specify which X chromosome undergoes inactivation.…”

A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas

“…One of the better elucidated large ncRNAs is Xist (X chromosome inactive specific transcript) that presents as a 17-kb (human) and a 15-kb (mouse) molecule responsible for somatic X-chromosome dosage compensation (Brockdorff et al, 1992;Brown et al, 1992;Plath et al, 2002). Another example is a paternally imprinted gene H19 (O'neill, 2005), with a conserved secondary structure but non-conserved ORFs, that functions as a tumor suppressor in some tumor types and may play a significant role in tumorigenesis in other types (Steenman et al, 1994;Lottin et al, 2002;Manoharan et al, 2003).…”

Silence of the fathers: Early X inactivation

“…(16,17) Additional histone modifications associated with the inactive X include hypoacetylation of H3 and H4, hypomethylation of H3K4, methylation of H3K9, and association of macro H2A. (18) These chromatin modifications are thought to contribute to and ensure the maintenance of X inactivation. Based on beautiful antibody staining of early embryos from the 4-cell stage onward, Okamoto et al have established the sequence of these histone modifications in early mouse development (2) (Fig.…”