Controlling X-inactivation in mammals: what does the centre hold?

doi:10.1016/j.semcdb.2003.09.014

Seminars in Cell & Developmental Biology

Volume 14, Issue 6, December 2003, Pages 331-340

https://doi.org/10.1016/j.semcdb.2003.09.014 Get rights and content

Abstract

Controlling gene expression is one of the most fundamental task of living organisms, from prokaryotes to higher eukaryotes, in order to develop, grow, and reproduce in an ever changing environment. In many cases, the expression status of a given gene is controlled independently of that of its neighbours through localised cis DNA elements responsible for the recruitment of specific factors and enzymatic activities. However, in a growing number of cases, genomic regions including several genes have been shown to be regulated in a coordinated manner. X-chromosome inactivation, the dosage compensation mechanism encountered in mammals, is one of the most striking example of such coordinated gene regulation. This process, which occurs at the chromosome-wide level, affecting many hundreds of genes, is under the control of a unique, cis acting region, termed the X-inactivation centre, whose complexity is just beginning to be unravelled.

Section snippets

Generalities about X-chromosome inactivation

The emergence of X-chromosome inactivation (X-inactivation) in mammals is though to be linked to the need to compensate for the imbalance in X-linked gene-products between males (with one X chromosome) and females (with two Xs). Variation in the gene content of the X chromosome in different mammalian species is accompanied by differences in the exact form that takes the X-inactivation process. Successive accretions of autosomal material to the X chromosome [1], by increasing the number of genes

Functional definition of the X-inactivation centre

The notion of a unique and cis-acting region of the X chromosome controlling most aspects of X-inactivation has come from the analysis of chromosomal rearrangements involving the X chromosome [4], [8]. It was shown in the case of X/autosome translocations that only one of the two products could be inactivated, indicating that inactivation could not be initiated by just any X-linked sequence, but rather was dependent on the presence of a specific region of the X chromosome. By analysing many

Physical definition of the murine X-inactivation centre

Based on the analysis of human X chromosome rearrangements, a candidate region of some 700–1200 kb has been defined as the murine X-inactivation centre (Fig. 1). More than 700 kb of fully annotated sequence for this region has recently been obtained [17]. In silico analysis followed by experimental verification has not only confirmed the existence of several previously characterized genes, but has also identified multiple new, and in some cases atypical transcription units [17]. Of the 12 known

Xist, the key player of X-inactivation and its antisense Tsix

Xist, the first gene found to map within the Xic candidate region, encodes a long spliced, poly-adenylated transcript, that has the unique property of being expressed exclusively from the inactive X chromosome in female somatic cells [24]. One of its most outstanding feature is its ability to coat entirely the inactive X-chromosome, suggesting that Xist acts as a structural RNA [25], [26]. Prior to X-inactivation, in undifferentiated cells, Xist is expressed at low levels from each X

Gain of function approaches toward a functional characterisation of the Xic

The Xic has was originally defined by comparing several chromosomal rearrangements involving the X chromosome for the ability of the resulting chromosomal products to be inactivated. However, the limited number of rearrangements available did not allow the minimal region necessary and sufficient to induce X-inactivation to be determined with great accuracy. One approach undertaken by several research groups in order to gain further insight into the minimal size of the Xic exploits a transgenic

Loss of function approaches toward a functional characterisation of the Xic

Results from both deletions of the Xist gene and Xist cDNA transgenesis concur to indicate that the counting functions of the Xic must be encoded by elements lying outside of Xist. The deletion of Xist in female ES cells for instance, does not interfere with counting, as inactivation of a single X is still initiated [30], [31]. Reciprocally, upregulation of Xist transcription from an inducible Xist cDNA transgene, whilst it induces silencing in cis independently of the presence of flanking DNA

Genomic and genetic comparison of the human and mouse XIC/Xic

Whilst X-inactivation occurs in all species of mammals, major differences are known to exist between different species. In marsupials and monotremes for instance, the paternal X is preferentially inactivated in all tissues [5] whereas in the mouse, only extraembryonic tissues display imprinted X-inactivation [58]. In human, both the paternal and maternal XIST genes appear to be equally transcribed in preimplantation embryos [59]. Such differences underline the interest of comparing the Xic

Acknowledgements

This review refers in part to results obtained in the Mouse Molecular Genetics Unit, which was partly financed by the ARC.

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