X Inactivation Counting and Choice Is a Stochastic Process: Evidence for Involvement of an X-Linked Activator

• Published in: Cell Vol. 132; no. 3; pp. 410 - 421
• Main Authors: Monkhorst, Kim, Jonkers, Iris, Rentmeester, Eveline, Grosveld, Frank, Gribnau, Joost
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08-02-2008
• Subjects: Animals; Cell Differentiation; Cell Line; CELLBIO; DEVBIO; Diploidy; Embryonic Stem Cells; Epigenesis, Genetic; Female; Genes, X-Linked; In Situ Hybridization, Fluorescence; Male; Mice; Polyploidy; Probability; Regulatory Elements, Transcriptional; RNA, Long Noncoding; RNA, Untranslated - genetics; Sequence Deletion; STEMCELL; Stochastic Processes; X Chromosome - metabolism; X Chromosome Inactivation; CELLBIO; STEMCELL; DEVBIO
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2007.12.036

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.