Abstract
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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | e105862 |
| Tidsskrift | EMBO Journal |
| Vol/bind | 40 |
| Udgave nummer | 22 |
| Antal sider | 16 |
| ISSN | 0261-4189 |
| DOI | |
| Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:We acknowledge David Kelly from the COIL facility, WTCCB, University of Edinburgh; Emerald Perlas from the Histology Facility of the Epigenetics & Neurobiology Unit, EMBL Rome; Violetta Parimbeni for mouse husbandry, (Epigenetics & Neurobiology Unit, EMBL Rome). We thank Phil Avner (Epigenetics & Neurobiology Unit, EMBL Rome) for advice, reagents, support, discussions and critically reading the manuscript. Rafael Galupa (EMBL Heidelberg) and Jacqueline Mermoud (University of Marburg) are thanked for critically reading the manuscript. Titia de Lange (The Rockefeller University) is thanked for initially supporting the generation of the knockout mice. Joost Gribnau and Cristina Gontan (Erasmus MC, University Medical Center, Rotterdam) are thanked for the Xist‐luciferase reporter plasmid. Andrew Jarman and Petra zur Lage (Centre for Discovery Brain Sciences, Edinburgh) and Sally Lowell (MRC Centre for Regenerative Medicine, Edinburgh) are all thanked for providing reagents. EE received funding from the European Union’s Horizon 2020 research and the Marie Skłodowska‐Curie Individual Fellowship grant agreement No. 660985 and from the ERC consolidator award 726130 to SCBB. LP and LB were funded by the ERC consolidator award 726130 to SBCB. RF was funded by the EMBL Interdisciplinary Postdoc (EIPOD) fellowship under Marie Curie Actions (COFUND). GK acknowledges funding from the IMPRS‐BAC. AC is funded by a Rett Syndrome Research Trust (RSRT), BARTSCHARITY grants, and intramural QMUL support. Rif1
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© 2021 The Authors.