Revisiting the consequences of deleting the X inactivation center.

Mammalian cells equalize X-linked dosages between the male (XY) and female (XX) sexes by silencing one X chromosome in the female sex. This process, known as "X chromosome inactivation" (XCI), requires a master switch within the X inactivation center (). The spans several hundred kilobases in the mouse and includes a number of regulatory noncoding genes that produce functional transcripts. Over three decades, transgenic and deletional analyses have demonstrated both the necessity and sufficiency of the to induce XCI, including the steps of X chromosome counting, choice, and initiation of whole-chromosome silencing. One recent study, however, reported that deleting the noncoding sequences of the surprisingly had no effect for XCI and attributed a sufficiency to drive counting to the coding gene, Here, we revisit the question by creating independent deletion cell lines. Multiple independent clones carrying heterozygous deletions of the display an inability to up-regulate Xist expression, consistent with a counting defect. This defect is rescued by a second site mutation in occurring , bypassing the defect in counting. These findings reaffirm the essential nature of noncoding elements for the initiation of XCI.