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

Barakat, Tahsin Stefan; Loos, Friedemann; Staveren, Selma van; Myronova, Elvira; Ghazvini, Mehrnaz; Grootegoed, J. Anton; Gribnau, Joost

doi:10.1016/j.molcel.2014.02.006

Cited by 67 publications

(90 citation statements)

References 30 publications

(89 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…68 A recent study suggested that Jpx acts only in cis. 72 This interpretation, however, is complicated by the nature of the deletional analysis, which involved very large deletions of multiple genes in cis. Further investigations will be needed to resolve the discrepancy.…”

Section: -70mentioning

confidence: 99%

See 1 more Smart Citation

Coupling of X-Chromosome reactivation with the pluripotent stem cell state

Payer

Lee

2014

RNA Biology

View full text Add to dashboard Cite

X -chromosome inactivation (XCI)in female mammals is a dramatic example of epigenetic gene regulation, which entails the silencing of an entire chromosome through a wide range of mechanisms involving noncoding RNAs, chromatin-modifications, and DNAmethylation. While XCI is associated with the differentiated cell state, it is reversed by X-chromosome reactivation (XCR) ex vivo in pluripotent stem cells and in vivo in the early mouse embryo and the germline. Critical in the regulation of XCI vs. XCR is the X-inactivation center, a multigene locus on the X-chromosome harboring several long noncoding RNA genes including, most prominently, Xist and Tsix. These genes, which sit at the top of the XCI hierarchy, are by themselves controlled by pluripotency factors, coupling XCR with the naïve pluripotent stem cell state. In this point-of-view article we review the latest findings regarding this intricate relationship between cell differentiation state and epigenetic control of the X-chromosome. In particular, we discuss the emerging picture of complex multifactorial regulatory mechanisms, ensuring both a finetuned and robust X-reactivation process.

show abstract

Section: -70mentioning

confidence: 99%

“…58,65,72 The differentiation-induced upregulation of RNF12 suggested that like Xist, Rnf12 might be repressed by the pluripotency factor network in undifferentiated cells. Indeed, ChIP-experiments confirmed binding of OCT4, SOX2, NANOG and PRDM14 to the upstream regulatory region of Rnf12 in ESCs.…”

Section: -70mentioning

confidence: 99%

Coupling of X-Chromosome reactivation with the pluripotent stem cell state

Payer

Lee

2014

RNA Biology

View full text Add to dashboard Cite

show abstract

“…Subsequent studies showed that in the mouse and Xenopus RLIM/Rlim is an important protein involved in early embryogenesis [10][11][12], e.g., lung, brain, and neural tube development [13]. In addition, mouse RLIM activates X-chromosome inactivation (XCI) [14][15][16]. In vitro studies in embryonic stem cells indicated that RLIM targets the XCI inhibitor REX1 for proteasomal degradation via polyubiquitination [2], and that at least one functional copy of Rlim is required to reduce REX1 levels sufficiently for initiation of XCI [17].…”

Section: Introductionmentioning

confidence: 99%

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

et al. 2018

Self Cite

View full text Add to dashboard Cite

RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes cosegregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.

show abstract

“…is able to undergo Xist RNA coating and inactivation in differentiating ESCs (68). These observations open the possibility of an alternate X-linked dosage-sensing mechanism.…”

Section: δTsixmentioning

confidence: 82%

“…As a consequence of this coupling, Xist is believed to be selectively upregulated from one of the two Xs (63-65), presumably through a transvection-like mechanism (62). However, deletions of all Xic elements thought to take part in X homolog pairing nevertheless result in Xist induction and inactivation of one of the two Xs in female cells (30,33,(66)(67)(68).…”

Section: δTsixmentioning

confidence: 99%

Sex-specific silencing of X-linked genes by Xist RNA

Gayen

Maclary

Hinten

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

X-inactive specific transcript (Xist) long noncoding RNA (lncRNA) is thought to catalyze silencing of X-linked genes in cis during X-chromosome inactivation, which equalizes X-linked gene dosage between male and female mammals. To test the impact of Xist RNA on X-linked gene silencing, we ectopically induced endogenous Xist by ablating the antisense repressor Tsix in mice. We find that ectopic Xist RNA induction and subsequent X-linked gene silencing is sex specific in embryos and in differentiating embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs). A higher frequency of X ΔTsix Y male cells displayed ectopic Xist RNA coating compared with X ΔTsix X female cells. This increase reflected the inability of X ΔTsix Y cells to efficiently silence X-linked genes compared with X ΔTsix X cells, despite equivalent Xist RNA induction and coating. Silencing of genes on both Xs resulted in significantly reduced proliferation and increased cell death in X ΔTsix X female cells relative to X ΔTsix Y male cells. Thus, whereas Xist RNA can inactivate the X chromosome in females it may not do so in males. We further found comparable silencing in differentiating X ΔTsix Y and 39,X ΔTsix (X ΔTsix O) ESCs, excluding the Y chromosome and instead implicating the X-chromosome dose as the source of the sexspecific differences. Because X ΔTsix X female embryonic epiblast cells and EpiSCs harbor an inactivated X chromosome prior to ectopic inactivation of the active X ΔTsix X chromosome, we propose that the increased expression of one or more X-inactivation escapees activates Xist and, separately, helps trigger X-linked gene silencing.inactivation represents a paradigm of epigenetic regulation and long noncoding RNA (lncRNA) function. In XX female cells, one of the two X chromosomes undergoes transcriptional silencing (1). Moreover, replicated copies of the active and inactive X chromosomes faithfully maintain their respective transcriptional states through many cell division cycles (2-5).X inactivation requires the X-inactive specific transcript (Xist) (6-8), a lncRNA that is selectively expressed from and physically coats the future inactive X chromosome (9-12). Xist RNA enables X-linked gene silencing by recruiting protein complexes to the inactive X (13-15). Female mouse embryos that inherit a paternal Xist mutation die due to defects in imprinted X inactivation of the paternal X chromosome in extraembryonic tissues (8,16,17). Xist is also required in the epiblast-derived embryonic cells, which undergo random X inactivation of either the maternal or the paternal X chromosome. Xist heterozygote fetal cells exhibit inactivation of only the X chromosome with an intact Xist locus, suggesting that Xist is necessary to choose the X chromosome to be inactivated (7,18,19). That the Xist-mutant X chromosome is not selected for inactivation, however, precludes assigning to Xist RNA a gene silencing role in the epiblast lineage.Ectopic expression studies have, however, demonstrated that Xist RNA can silence genes, albeit in a context-...

show abstract

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

Cited by 67 publications

References 30 publications

Coupling of X-Chromosome reactivation with the pluripotent stem cell state

Coupling of X-Chromosome reactivation with the pluripotent stem cell state

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Sex-specific silencing of X-linked genes by Xist RNA

Contact Info

Product

Resources

About