title: The trans-activator RNF12 and cis-acting elements effectuate X chromosome inactivation independent of X-pairing.
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.
authors.affiliation: Department of Reproduction and Development, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
authors.forename: Tahsin Stefan
authors.initials: TS
authors.lastname: Barakat
authors.affiliation: Department of Reproduction and Development, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Loos
authors.affiliation: Department of Reproduction and Development, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
authors.forename: Selma
authors.initials: S
authors.lastname: van Staveren
authors.affiliation: Department of Reproduction and Development, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
authors.forename: Elvira
authors.initials: E
authors.lastname: Myronova
authors.affiliation: Department of Reproduction and Development, Erasmus MC, University Medical Center, Rotterdam, The Netherlands; Erasmus Stem Cell Institute, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
authors.forename: Mehrnaz
authors.initials: M
authors.lastname: Ghazvini
authors.affiliation: Department of Reproduction and Development, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
authors.forename: J Anton
authors.initials: JA
authors.lastname: Grootegoed
authors.affiliation: Department of Reproduction and Development, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address: j.gribnau@erasmusmc.nl.
authors.forename: Joost
authors.initials: J
authors.lastname: Gribnau
mesh_terms: D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D023902:Chromosome Pairing; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D018345:Mice, Knockout; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D014960:X Chromosome; D049951:X Chromosome Inactivation
chemical_list: D062085:RNA, Long Noncoding; C465658:Tsix transcript, mouse; C077885:XIST non-coding RNA; C120758:Rlim protein, mouse; D044767:Ubiquitin-Protein Ligases