Heterogeneous gene expression from the inactive X chromosome: An X-linked gene that escapes X inactivation in some human cell lines but is inactivated in others

In mammalian females, most genes on one X chromosome are transcriptionally silenced as a result of X chromosome inactivation, Whereas it is well estab lished that some X-linked genes "escape'' X inactivation and are expressed from both active (Xa) and inactive (Xi) X chromosomes, most models for the chromosomal control of X-linked gene expression assume that the X inactivat ion status of a given gene is constant among different females within a pop ulation. In this report, we test the expression of human S-linked genes in primary cell lines from females with complete nonrandom X inactivation by u sing transcribed polymorphisms to distinguish Sa and Si expression, Six X-l inked genes used to document this assay system show ed monoallelic expressi on in all informative cell lines, consistent with X inactivation, However, a novel pattern of expression was observed for another gene, REP1; monoalle lic expression, indicating inactivation, was detected in some lines, wherea s biallelic expression, indicating escape from inactivation, H-as detected in others. Furthermore, levels of Si expression,varied among cell lines tha t expressed REP1, The cellular basis of Si expression uas examined by expre ssion assays in single cells. These data indicate that REP1 is expressed fr om the Xi in all cells, but that the level of expression relative to Sa lev els is reduced. These findings suggest that Si gene expression is under a p reviously unsuspected level of genetic or epigenetic control, likely involv ing local or regional changes in chromatin organization that determine whet her a gene escapes or is subject to X inactivation.