X inactivation counting and choice is a stochastic process: evidence for involvement of an X-linked activator

Cell. 2008 Feb 8;132(3):410-21. doi: 10.1016/j.cell.2007.12.036.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Line
  • Diploidy
  • Embryonic Stem Cells
  • Epigenesis, Genetic
  • Female
  • Genes, X-Linked*
  • In Situ Hybridization, Fluorescence
  • Male
  • Mice
  • Polyploidy
  • Probability
  • RNA, Long Noncoding
  • RNA, Untranslated / genetics
  • Regulatory Elements, Transcriptional
  • Sequence Deletion
  • Stochastic Processes
  • X Chromosome / metabolism*
  • X Chromosome Inactivation*

Substances

  • RNA, Long Noncoding
  • RNA, Untranslated
  • Tsix transcript, mouse
  • XIST non-coding RNA