title: RNF12 activates Xist and is essential for X chromosome inactivation.
abstract: In somatic cells of female placental mammals, one of the two X chromosomes is transcriptionally silenced to accomplish an equal dose of X-encoded gene products in males and females. Initiation of random X chromosome inactivation (XCI) is thought to be regulated by X-encoded activators and autosomally encoded suppressors controlling Xist. Spreading of Xist RNA leads to silencing of the X chromosome in cis. Here, we demonstrate that the dose dependent X-encoded XCI activator RNF12/RLIM acts in trans and activates Xist. We did not find evidence for RNF12-mediated regulation of XCI through Tsix or the Xist intron 1 region, which are both known to be involved in inhibition of Xist. In addition, we found that Xist intron 1, which contains a pluripotency factor binding site, is not required for suppression of Xist in undifferentiated ES cells. Analysis of female Rnf12⁻/⁻ knockout ES cells showed that RNF12 is essential for initiation of XCI and is mainly involved in the regulation of Xist. We conclude that RNF12 is an indispensable factor in up-regulation of Xist transcription, thereby leading to initiation of random XCI.
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.forename: Nilhan
authors.initials: N
authors.lastname: Gunhanlar
authors.forename: Cristina Gontan
authors.initials: CG
authors.lastname: Pardo
authors.forename: Eskeatnaf Mulugeta
authors.initials: EM
authors.lastname: Achame
authors.forename: Mehrnaz
authors.initials: M
authors.lastname: Ghazvini
authors.forename: Ruben
authors.initials: R
authors.lastname: Boers
authors.forename: Annegien
authors.initials: A
authors.lastname: Kenter
authors.forename: Eveline
authors.initials: E
authors.lastname: Rentmeester
authors.forename: J Anton
authors.initials: JA
authors.lastname: Grootegoed
authors.forename: Joost
authors.initials: J
authors.lastname: Gribnau
mesh_terms: D000818:Animals; D053595:Embryonic Stem Cells / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D007438:Introns / Q000235:genetics; D008297:Male; D051379:Mice; D000071317:Nanog Homeobox Protein; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases; D049951:X Chromosome Inactivation / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D012097:Repressor Proteins; C465658:Tsix transcript, mouse; C077885:XIST non-coding RNA; C120758:Rlim protein, mouse; D044767:Ubiquitin-Protein Ligases