X inactivation counting and choice is a stochastic process: evidence for involvement of an X-linked activator.
Female mammalian cells achieve dosage compensation of X-encoded genes by X chromosome inactivation (XCI). This process is thought to involve X chromosome counting and choice. To explore how this process is initiated, we analyzed XCI in tetraploid XXXX, XXXY, and XXYY embryonic stem cells and found that every X chromosome within a single nucleus has an independent probability to initiate XCI. This finding suggests a stochastic mechanism directing XCI counting and choice. The probability is directly proportional to the X chromosome:ploidy ratio, indicating the presence of an X-encoded activator of XCI, that itself is inactivated by the XCI process. Deletion of a region including Xist, Tsix, and Xite still results in XCI on the remaining wild-type X chromosome in female cells. This result supports a stochastic model in which each X chromosome in a nucleus initiates XCI independently and positions an X-encoded trans-acting XCI-activator outside the deleted region.
Monkhorst
Kim
K
Department of Cell Biology, Erasmus Medical Center, P.O. Box 2040, Rotterdam 3000 CA, The Netherlands; Department of Reproduction and Development, Erasmus Medical Center, P.O. Box 2040, Rotterdam 3000 CA, The Netherlands.
Jonkers
Iris
I
Rentmeester
Eveline
E
Grosveld
Frank
F
Gribnau
Joost
J
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D004171:Diploidy; D053595:Embryonic Stem Cells; D044127:Epigenesis, Genetic; D005260:Female; D050172:Genes, X-Linked; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D011123:Polyploidy; D011336:Probability; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics; D050436:Regulatory Elements, Transcriptional; D017384:Sequence Deletion; D013269:Stochastic Processes; D014960:X Chromosome / Q000378:metabolism*; D049951:X Chromosome Inactivation
D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C465658:Tsix transcript, mouse; C077885:XIST non-coding RNA