Silencing of the Mammalian X Chromosome

Abstract

Mammalian X chromosome inactivation is one of the most striking examples of epigenetic gene regulation. Early in development one of the pair of approximately 160-Mb X chromosomes is chosen to be silenced, and this silencing is then stably inherited through subsequent somatic cell divisions. Recent advances have revealed many of the chromatin changes that underlie this stable silencing of an entire chromosome. The key initiator of these changes is a functional RNA, XIST, which is transcribed from, and associates with, the inactive X chromosome, although the mechanism of association with the inactive X and recruitment of facultative heterochromatin remain to be elucidated. This review describes the unique evolutionary history and resulting genomic structure of the X chromosome as well as the current understanding of the factors and events involved in silencing an X chromosome in mammals.

Symmetry-Breaking Model forX-Chromosome Inactivation

“…This explains biased XCI in embryonic tissues resulting from allelic differences in Xic sequences, (e.g., in the Xce locus [15] or other regions [1,2,3]). XCI in female cells and lack of XCI in male cells could derive from a similar mechanism.…”

“…Our model describes how a 'blocking factor' complex is self-assembled and why only one is formed out of many diffusible molecules, resulting in a spontaneous symmetry breaking (SB) in the binding to two identical chromosomes. These results are used to derive a scenario of biological implications describing all current experimental evidences, e.g., the importance of colocalization.X chromosome inactivation (XCI) is the phenomenon in female mammal early embryo cells by which one of their two X chromosomes, randomly chosen, is transcriptionally silenced, and epigenetically inherited in descendants, to equalize the dosage of X genes products with respect to males [1,2,3]. Crucial aspects of this chromosome-wide stochastic regulatory mechanism, necessary to survival, still elude comprehension despite being the focus of substantial interest for their important scientific and medical implication (see [1,2,3] and Ref.s therein).…”

“…Crucial aspects of this chromosome-wide stochastic regulatory mechanism, necessary to survival, still elude comprehension despite being the focus of substantial interest for their important scientific and medical implication (see [1,2,3] and Ref.s therein). Starting from the important discovery of X colocalization during XCI establishment [4,5], in this paper we propose a Statistical Mechanics model of the early steps of XCI.…”

“…Actually, XCI is a multistep process involving [1,2,3]: "counting" the number of the X chromosomes of the cell, "choice" of the inactive X, its silencing and maintenance. Silencing and maintenance start being understood: the former is induced by the action of the Xist gene transcript, and maintenance of the inactive state is a paradigm of epigenetic inheritance [3,6].…”

“…Current models postulate the existence of a "blocking factor" (BF) [1,2,3], a complex made of X and autosomal factors, binding to the Xic of just one chromosome per diploid cell preventing its inactivation, as the second unprotected Xic in a female cell is inactivated by default. Multiple factors models were proposed as well [8,9].…”