Histone H4 acetylation analyses in patients with polysomy X: implications for the mechanism of X inactivation

Abstract

In humans, it is thought that the X-inactivation phenomenon occurs no matter how many X chromosomes are present, and that only one of them remains active. Nevertheless, individuals who have an abnormal number of X chromosomes show a wide spectrum of abnormalities, which increase with the number of X chromosomes present in a given individual. It has been shown that the inactive X chromosome in female mammals is distinguished by a lack of histone H4 acetylation, and that this could be used as an accessible marker for distinguishing between Xi and Xa in spreads of metaphase chromosomes. We studied three X-polysomic patients for the presence of active chromatin by analysis of histone H4 acetylation on unfixed metaphase spreads. Using antisera to H4 acetylated at lysines 16, 8 and 5, respectively, we observed frequencies different from those expected from cells with only one underacetylated X chromosome. In particular, when antiserum to H4 acetylated at lysine 16 was used about 90% of the cells showed acetylation of all X chromosomes. This suggests a possible disturbance in the deacetylation process, probably due to the presence of multiple Xs.

X-chromosome inactivation: molecular mechanisms from the human perspective

“…The increased mortality for individuals with supernumerary X's could result from over-expression of any of the genes that escape XCI, however, it is also possible that there are limitations to the ability of cells to inactivate additional X's. There are increasing abnormalities with increased number of supernumerary X's, and the extra Xi's in polysomy X were reported to have less histone acetylation depletion compared with the single Xi in females with a normal karyotype (Leal et al 1998).…”

Forming facultative heterochromatin: silencing of an X chromosome in mammalian females

“…Figure 1 demonstrates that rather than being a simple stepwise accumulation of chromatin changes that lead to silencing, X-chromosome inactivation involves a complex interaction amongst the various events. Indeed, the inactive X can be retained after loss of XIST expression [33,34], changes in replication timing [101], altered histone modifications [194], loss of the MCB [32] or the absence/reduction of DNA methylation (as in marsupials [3], ICF syndrome [189] and extraembryonic tissues [162]). Reactivation of individual genes occurs at a higher frequency when a feature is disrupted, such as in somatic cell hybrids that have delocalized XIST [159] or marsupials that lack DNA hypermethylation [3].…”

Histone acetylation and disease

“…While the exact mechanism of this inactivation is not yet clear, there is a compelling link between histone underacetylation and inactivation of the X chromosome (for a review see [8]). Interestingly, in patients containing aberrant copy numbers of the X chromosome (polysomy X), incomplete deacetylation of all X chromosomes was observed [9]. The syndrome of fragile X chromosome provides another link between histone acetylation and human hereditary disorders and will be discussed below.…”