RIF1 and KAP1 differentially regulate the choice of inactive versus active X chromosomes
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RIF1 and KAP1 differentially regulate the choice of inactive versus active X chromosomes. / Enervald, Elin; Powell, Lynn Marie; Boteva, Lora; Foti, Rossana; Blanes Ruiz, Nerea; Kibar, Gözde; Piszczek, Agnieszka; Cavaleri, Fatima; Vingron, Martin; Cerase, Andrea; Buonomo, Sara B.C.
In: EMBO Journal, Vol. 40, No. 22, e105862 , 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - RIF1 and KAP1 differentially regulate the choice of inactive versus active X chromosomes
AU - Enervald, Elin
AU - Powell, Lynn Marie
AU - Boteva, Lora
AU - Foti, Rossana
AU - Blanes Ruiz, Nerea
AU - Kibar, Gözde
AU - Piszczek, Agnieszka
AU - Cavaleri, Fatima
AU - Vingron, Martin
AU - Cerase, Andrea
AU - Buonomo, Sara B.C.
N1 - Publisher Copyright: © 2021 The Authors.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - KAP1
KW - RIF1
KW - Tsix
KW - X chromosome inactivation
KW - Xist
U2 - 10.15252/embj.2020105862
DO - 10.15252/embj.2020105862
M3 - Journal article
C2 - 34786738
AN - SCOPUS:85119051236
VL - 40
JO - E M B O Journal
JF - E M B O Journal
SN - 0261-4189
IS - 22
M1 - e105862
ER -
ID: 285313723