The Trans-Activator RNF12 and Cis-Acting Elements Effectuate X Chromosome Inactivation Independent of X-Pairing

Stefan Barakat, Friedmann Loos, Selma Staveren, E Myronova, Mehrnaz Ghazvini, Anton Grootegoed, Joost Gribnau

Research output: Contribution to journalArticleAcademic

52 Citations (Scopus)

Abstract

X chromosome inactivation (XCI) in female placental mammals is a vital mechanism for dosage compensation between X-linked and autosomal genes. XCI starts with activation of Xist and silencing of the negative regulator Tsix, followed by cis spreading of Xist RNA over the future inactive X chromosome (Xi). Here, we show that XCI does not require physical contact between the two X chromosomes (X-pairing) but is regulated by trans-acting diffusible factors. We found that the X-encoded trans-acting and dose-dependent XCI-activator RNF12 acts in concert with the cis-regulatory region containing Jpx, Ftx, and Xpr to activate Xist and to overcome repression by Tsix. RNF12 acts at two subsequent steps; two active copies of Rnf12 drive initiation of XCI, and one copy needs to remain active to maintain XCI toward establishment of the Xi. This two-step mechanism ensures that XCI is very robust and fine-tuned, preventing XCI of both X chromosomes.
Original languageUndefined/Unknown
Pages (from-to)965-978
Number of pages14
JournalMolecular Cell
Volume53
Issue number6
DOIs
Publication statusPublished - 2014

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