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

Elin Enervald, Lynn Marie Powell, Lora Boteva, Rossana Foti, Nerea Blanes Ruiz, Gözde Kibar, Agnieszka Piszczek, Fatima Cavaleri, Martin Vingron, Andrea Cerase, Sara B.C. Buonomo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Article numbere105862
Number of pages41
JournalEMBO Journal
DOIs
Publication statusPublished - 17 Nov 2021

Keywords / Materials (for Non-textual outputs)

  • KAP1
  • RIF1
  • Tsix
  • X chromosome inactivation
  • Xist

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