X inactivation in triploidy and trisomy: the search for autosomal transfactors that choose the active X

Abstract

Only one X chromosome functions in diploid human cells irrespective of the sex of the individual and the number of X chromosomes. Yet, as we show, more than one X is active in the majority of human triploid cells. Therefore, we suggest that (i) the active X is chosen by repression of its XIST locus, (ii) the repressor is encoded by an autosome and is dosage sensitive, and (iii) the extra dose of this key repressor enables the expression of more than one X in triploid cells. Because autosomal trisomies might help locate the putative dosage sensitive trans-acting factor, we looked for two active X chromosomes in such cells. Previously, we reported that females trisomic for 18 different human autosomes had only one active X and a normal inactive X chromosome. Now we report the effect of triplication of the four autosomes not studied previously; data about these rare trisomies -full or partial -were used to identify autosomal regions relevant to the choice of active X. We find that triplication of the entire chromosomes 5 and 11 and parts of chromosomes 1 and 19 is associated with normal patterns of X inactivation, excluding these as candidate regions. However, females with inherited triplications of 1p21.3 -q25.3, 1p31 and 19p13.2 -q13.33 were not ascertained. Thus, if a single key dose-sensitive gene induces XIST repression, it could reside in one of these locations. Alternatively, more than one dosage-sensitive autosomal locus is required to form the repressor complex.

X-chromosome inactivation: molecular mechanisms from the human perspective

“…XaXaXi or XaXiXi), has led to models for XCI 'count' that involve dosage of autosomal factors. Such a singular locus has not been identiWed by the study of autosomal trisomies, although there remain some autosomal segments that have not been identiWed in a trisomic region (Migeon et al 2008). …”

Intestinal Atresia, Encephalocele, and Cardiac Malformations in Infants with 47,XXX: Expansion of the Phenotypic Spectrum and a Review of the Literature

“…It has been shown, however, that more than one X chromosome is active in the majority of human triploid cells [20] . It has been suggested that the active X is selected by repression of its XIST locus: a dosage-sensitive repressor is encoded by an autosome, and the extra dose of this key repressor enables the expression of more than one X in triploid cells [20] .…”

“…It has been shown, however, that more than one X chromosome is active in the majority of human triploid cells [20] . It has been suggested that the active X is selected by repression of its XIST locus: a dosage-sensitive repressor is encoded by an autosome, and the extra dose of this key repressor enables the expression of more than one X in triploid cells [20] . Since females with 47,XXX carry a normal set of diploid autosomes, it could be hypothesized that rare copy number variants in an autosomal repressor cause an increased expression of this repressor which results in more than one X chromosome being activated.…”

The single active X in human cells: evolutionary tinkering personified

“…Yet, XIST has all the hallmarks of a housekeeping gene, ubiquitously expressed, with a 5 0 CpG island; it is expressed, from all X chromosomes in the zygote of either sex, albeit at low levels, until the time in embryogenesis when the locus on the future active X is turned off, and methylated in both males and females. In addition, the study of 69, XXX and 69, XXY triploid cells provides compelling evidence that it is the active X, rather than the inactive X that is chosen (Migeon et al 2008) (Fig. 2).…”

“…2). Despite the equal dose of X-linked Rnf12, one X is inactive in 47, XXY diploid cells, whereas, in 69 XXY cells, neither X may be inactivated (Migeon et al 2008).…”