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Releasing the Break on X Chromosome Inactivation: Rnf12/RLIM Targets REX1 for Degradation

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Releasing the Break on X Chromosome Inactivation: Rnf12/RLIM Targets REX1 for Degradation npg 1524 Cell Research (2012) 22:1524-1526. npg © 2012 IBCB, SIBS, CAS All rights reserved 1001-0602/12 $ 32.00 RESEARCH HIGHLIGHT www.nature.com/cr Releasing the break on X chromosome inactivation: Rnf12/RLIM targets REX1 for degradation Ingolf Bach1, 2 1Program in Gene Function & Expression, 2Program in Molecular Medicine, University of Massachusetts Medical School, Worces- ter, MA 01605, USA Cell Research (2012) 22:1524-1526. doi:10.1038/cr.2012.98; published online 26 June 2012 One of the two X chromosomes a transcriptional coregulator [3]. Rnf12/ provided that Rnf12/RLIM exerts its in cells of female mammals is tran- RLIM has been identified as a ubiquitin functions for XCI initiation via promot- scriptionally silenced in a process ligase [4] that regulates activities of ing Xist expression [8, 10, 11] in a dose- known as X chromosome inactivation different classes of transcription fac- dependent manner [10]. Intriguingly, (XCI). Initiation of XCI is regulated tors [5, 6] in part by adjusting cellular cellular Rnf12/RLIM levels increase at by the ubiquitin ligase Rnf12/RLIM, levels of various nuclear cofactors via the onset of rXCI [10, 11], likely due to but the mechanisms by which Rnf12/ the ubiquitin/proteasome system (UPS) a release from transcriptional repression RLIM mediates this process has been [4, 7]. In female mice, sex-specific by pluripotency factors [12]. Together, a mystery. A recent study by Gontan parent-of-origin effects have been re- these studies indicate crucial functions et al. shows that Rnf12/RLIM targets ported upon Rnf12 deletion. Deletion of Rnf12/RLIM for the initiation of XCI REX1, an inhibitor of XCI, for pro- of the maternal Rnf12 allele in oocytes via activation of Xist. teasomal degradation, providing an results in early embryonic lethality However, these studies left unan- answer to this question. specifically in female embryos due to swered the question of how Rnf12/ To achieve dosage compensation, fe- a failure to develop extraembryonic RLIM promotes the activation of Xist. male mammals silence one of their two trophoblast tissues in the placenta [8]. In A recent study has addressed this point sex chromosomes in a process called contrast, in pregnant and lactating adult [13]. Gontan et al. used affinity purifica- X chromosome inactivation (XCI). In females Rnf12/RLIM expressed from tion followed by mass spectrometry to mice two forms of XCI exist: In 2-4 the paternal allele serves as a survival identify the transcription factor REX1 cell staged embryos, imprinted XCI factor specifically for milk-producing as a major interaction partner of Flag- (iXCI) results in exclusive silencing of alveolar cells in mammary glands [9]. tagged Rnf12/RLIM in ESC nuclei. In the paternal X (Xp). Around implanta- Thus, Rnf12 functions as a sex-specific these cells, REX1 appears to repress tion, female epiblast cells that give epigenetic regulator in female mouse genes that promote differentiation [14] rise to somatic tissues reactivate the nurturing tissues. and its expression correlates with the silenced Xp and undergo random XCI In an embryonic stem cell (ESC) pluripotent ESC state [15]. In an el- (rXCI), which inactivates the Xp or model, Rnf12/RLIM has been identified egant series of experiments, the authors the maternal X (Xm) with equal prob- as a major regulator for the initiation of showed that endogenous Rnf12/RLIM ability. Both forms of XCI require the rXCI. Indeed, forced overexpression interacts with, polyubiquitinates, and long non-coding Xist RNA, which coats of Rnf12/RLIM triggers ectopic Xist targets REX1 for degradation via the the inactive X chromosome (Xi) from clouds in male and female ESCs [10], UPS, thereby dynamically adjusting which it is transcribed [1, 2]. and homozygous deletion of Rnf12 levels of REX1 in various cell types The X-linked gene Rnf12 encodes resulted in a failure to initiate rXCI including ESCs. In agreement with the RING finger protein Rnf12/RLIM, [11]. In mice, the early lethality of these results, the upregulation of Rnf12/ female embryos upon deletion of the RLIM upon differentiation of ESCs was maternal Rnf12 allele was shown to be accompanied with a downregulation Correspondence: Ingolf Bach the consequence of defective initiation of REX1. While Rnf12/RLIM appears E-mail: [email protected] of iXCI [8]. Strong evidence has been to be a major regulator of REX1 dur- Cell Research | Vol 22 No 11 | November 2012 npg 1525 ing differentiation, the authors also ESCs, the authors suggest that REX1 and exciting mechanisms of epigenetic observed downregulation of REX1 in may function by activating Tsix expres- regulation. ESCs lacking Rnf12/RLIM, indicat- sion. Based on these results, the scenario ing that other proteins contribute to for female ESC differentiation and XCI References the reduction of REX1 levels upon would be as follows: Differentiation- 1 Augui S, Nora EP, Heard E. Regulation ESC differentiation. Interestingly, the induced downregulation of pluripotency of X-chromosome inactivation by the authors showed that the RING finger factors trigger the upregulation of Rnf12 X-inactivation centre. Nat Rev Genet of RLIM, which mediates its ubiquitin transcription and an increase in cellular 2011; 12:429-442. ligase activity, plays important roles in Rnf12/RLIM levels. Lower cellular 2 Jeon Y, Sarma K, Lee JT. New and the Rnf12/RLIM-induced activation of levels of REX1 due to its increased Xisting regulatory mechanisms of X ectopic XCI in male ESCs. proteasomal targeting by Rnf12/RLIM chromosome inactivation. Curr Opin To identify roles of REX1 in XCI, would then lead to downregulation of Genet Dev 2012; 22:62-71. 3 Bach I, Rodriguez-Esteban C, Carriere day-3-differentiated male ESCs ex- Tsix and activation of Xist transcription C, et al. RLIM inhibits functional pressing lower REX1 levels (+/– for followed by initiation of XCI. Due to the activity of LIM homeodomain Rex1) or female ESCs overexpressing fact that similar to Xist, Rex1 is found transcription factors via recruitment of REX1 were examined for XCI as mea- only in placental mammals but not in the histone deacetylase complex. Nat sured by the occurrence of Xist clouds marsupials that also lack Xist-mediated Genet 1999; 22:394-399. coating an X chromosome. Indeed, XCI, the authors propose that Xist and 4 Ostendorff HP, Peirano RI, Peters MA, whereas a significant number of the Rex1 may have co-evolved with the et al. Ubiquitination-dependent cofac- tor exchange on LIM homeodomain male Rex1+/– ESCs underwent ectopic appearance of an Xist-dependent XCI transcription factors. Nature 2002; XCI, REX1-overexpressing female mechanism. 416:99-103. ESCs experienced severe inhibition While this report identifies important 5 Gungor C, Taniguchi-Ishigaki N, Ma of XCI. Importantly, knockdown of mechanisms of Rnf12/RLIM functions H, et al. Proteasomal selection of Rex1 in Rnf12–/– ESCs resulted in a during XCI activation, it also raises multiprotein complexes recruited by significant rescue of XCI. These results several questions. Going forward, one LIM homeodomain transcription fac- reveal functions of REX1 downstream of the most pressing question con- tors. Proc Natl Acad Sci USA 2007; 104:15000-15005. of Rnf12, directly linking the functions cerns the relevance of the Rnf12-Rex1 6 Johnsen SA, Gungor C, Prenzel T, et al. of both proteins during XCI and the regulatory module for XCI in vivo as Regulation of estrogen-dependent tran- formation of Xist clouds. seemingly conflicting results have been scription by the LIM cofactors CLIM Using chromatin immunoprecipita- reported for the requirement of Rnf12/ and RLIM in breast cancer. Cancer Res tion in undifferentiated ESCs, Gontan RLIM for the initiation of rXCI. In an 2009; 69:128-136. et al. [13] detected REX1 occupancy ES cell model Rnf12/RLIM is essen- 7 Bach I, Ostendorff HP. Orchestrating of promoter/regulatory elements of the tial for initiation of rXCI [11] and the nuclear functions: ubiquitin sets the Xist gene as well as those of Tsix, a gene results obtained by Gontan et al. [13] rhythm. Trends Biochem Sci 2003; 28:189-195. that overlaps with the Xist locus on the are largely based on the same model. 8 Shin J, Bossenz M, Chung Y, et al. X chromosome but is transcribed in the In contrast, evidence suggests that Maternal Rnf12/RLIM is required for antisense direction, thereby inhibiting Rnf12/RLIM may be dispensable for imprinted X-chromosome inactivation Xist transcription [2]. Indeed, consensus rXCI in mice [8] and Rex1–/– mice are in mice. Nature 2010; 467:977-981. recognition sequences for REX1 bind- viable with no apparent phenotype [16]. 9 Jiao B, Ma H, Shokhirev MN, et al. Pa- ing were found on regulatory elements Thus, it will be important to address ternal RLIM/Rnf12 is a survival factor of both genes, suggesting that this the functional requirement of Rnf12/ for milk-producing alveolar cells. Cell 2012; 149:630-641. transcription factor directly regulates RLIM in conjunction with REX1 for 10 Jonkers I, Barakat TS, Achame EM, the expression of these genes. To ad- rXCI in vivo and how they connect to et al. RNF12 is an X-encoded dose- dress this possibility, they performed the choice of which X chromosome to dependent activator of X chromosome transient cotranfections and detected a inactivate. Moreover, it will be inter- inactivation. Cell 2009; 139:999-1011. downregulation of Xist in cells overex- esting to examine whether the crucial 11 Barakat TS, Gunhanlar N, Pardo CG, pressing REX1, similar to cells that lack functions of Rnf12/RLIM during iXCI et al. RNF12 activates Xist and is es- Rnf12/RLIM. These results indicate that are also connected to Rex1 and whether sential for X chromosome inactivation. PLoS Genet 2011; 7:e1002001. REX1 functions as a repressor of Xist, targeted degradation of REX1 is the 12 Navarro P, Moffat M, Mullin NP, thereby inhibiting XCI.
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