4.8 Article

RIF1 and KAP1 differentially regulate the choice of inactive versus active X chromosomes

期刊

EMBO JOURNAL
卷 40, 期 24, 页码 -

出版社

WILEY
DOI: 10.15252/embj.2020105862

关键词

KAP1; RIF1; Tsix; X chromosome inactivation; Xist

资金

  1. European Union's Horizon 2020 research and the Marie Sklodowska-Curie Individual Fellowship [660985]
  2. ERC [726130]
  3. EMBL Interdisciplinary Postdoc (EIPOD) fellowship under Marie Curie Actions (COFUND)
  4. IMPRS-BAC
  5. Rett Syndrome Research Trust (RSRT)
  6. BARTSCHARITY grants
  7. intramural QMUL
  8. Marie Curie Actions (MSCA) [660985] Funding Source: Marie Curie Actions (MSCA)
  9. European Research Council (ERC) [726130] Funding Source: European Research Council (ERC)

向作者/读者索取更多资源

In the process of X chromosome choice in mice, RIF1 and KAP1 play fundamental roles, with the mutual exclusion between Tsix and RIF1, as well as between RIF1 and KAP1, establishing a self-sustaining loop that transforms the initial stochastic event into a stably inherited asymmetric X-chromosome state.
The onset of random X chromosome inactivation in mouse requires the switch from a symmetric to an asymmetric state, where the identities of the future inactive and active X chromosomes are assigned. This process is known as X chromosome choice. Here, we show that RIF1 and KAP1 are two fundamental factors for the definition of this transcriptional asymmetry. We found that at the onset of differentiation of mouse embryonic stem cells (mESCs), biallelic up-regulation of the long non-coding RNA Tsix weakens the symmetric association of RIF1 with the Xist promoter. The Xist allele maintaining the association with RIF1 goes on to up-regulate Xist RNA expression in a RIF1-dependent manner. Conversely, the promoter that loses RIF1 gains binding of KAP1, and KAP1 is required for the increase in Tsix levels preceding the choice. We propose that the mutual exclusion of Tsix and RIF1, and of RIF1 and KAP1, at the Xist promoters establish a self-sustaining loop that transforms an initially stochastic event into a stably inherited asymmetric X-chromosome state.

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