RLIM is dispensable for X-chromosome inactivation in the mouse embryonic epiblast

Shin, Jongdae; Wallingford, Mary C.; Gallant, Judith; Marcho, Chelsea; Jiao, Baowei; Byron, Meg; Bossenz, Michael; Lawrence, Jeanne B.; Jones, Stephen N.; Mager, Jesse; Bach, Ingolf

doi:10.1038/nature13286

Cited by 57 publications

(106 citation statements)

References 27 publications

(68 reference statements)

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“…Recently it was shown that RNF12 is dispensable for random XCI in vivo in the mouse epiblast and for normal epiblast development. 74 Therefore, many questions remain and further analysis will be required to shed light on the reason for these discrepancies.…”

Section: -70mentioning

confidence: 99%

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

Payer

Lee

2014

RNA Biology

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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.

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Section: -70mentioning

confidence: 99%

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

Payer

Lee

2014

RNA Biology

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“…It was identified as a negative regulator of LIM-HD transcription factors, acting either as a co-regulator via the recruitment of the Sin3A/histone deacetylase corepressor complex, or by targeting the cofactors for proteasomal degradation [8,9]. 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].…”

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

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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.

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“…The most studied role of RNF12 is its essential function in the first wave of paternally imprinted X-chromosome inactivation in mice. 9,13 All female carriers available for testing in our family have a completely skewed X-chromosome inactivation pattern in contrast to non-carriers. This could indicate that RLIM is essential for normal Xchromosome inactivation in humans as well.…”

Section: Discussionmentioning

confidence: 99%

“…11 It is crucial for normal embryonic development in some species 12 and for normal X inactivation in mice. 9,13 RNF12 mainly localizes to the cell nucleus, 11 where it regulates the levels of many proteins, including CLIM, LMO, HDAC2, TRF1, SMAD7 and REX1, by proteasomal degradation. 7,9,12,14 Thus, it modulates the activity of transcription factors, in particular those containing a LIM homeodomain, 15 and the formation of transcriptional multiprotein complexes.…”

Section: Discussionmentioning

confidence: 99%

Syndromic X-linked intellectual disability segregating with a missense variant in RLIM

et al. 2015

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We describe a three-generation Norwegian family with a novel X-linked intellectual disability (XLID) syndrome characterized by subtle facial dysmorphism, autism and severe feeding problems. By exome sequencing we detected a rare missense variant (c.1067A4G, p.(Tyr356Cys)) in the RLIM gene, in two affected male second cousins. Sanger sequencing confirmed the presence of the variant in the four affected males (none of whom were siblings) and in three mothers available for testing. The variant was not present in 100 normal Norwegian controls, has not been reported in variant databases and is deleterious according to in silico prediction tools. The clinical phenotype and the variant co-segregate, yielding a LOD score of 3.0 for linkage to the shared region (36.09 Mb), which contains 242 genes. No other shared rare variants on the X chromosome were detected in the two affected exome-sequenced individuals, and all female carriers had an extremely skewed X-chromosome inactivation pattern. RLIM encodes RING zinc finger protein 12 (RNF12), an ubiquitin ligase that is essential for X inactivation in mice and that acts as a co-regulator of a range of transcription factors, particularly those containing a LIM homeodomain. Tyrosine in position 356 in RNF12 is located within a highly conserved domain essential for binding such transcription factors. Expression of RNF12 is widespread during embryogenesis, and is particularly high in the outer layers of the cerebral cortex. Functional studies are needed to prove a definite causal relationship between the variant and the phenotype. Subsequent reports may confirm a role for RLIM variants in patients with XLID.

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RLIM is dispensable for X-chromosome inactivation in the mouse embryonic epiblast

Cited by 57 publications

References 27 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

Syndromic X-linked intellectual disability segregating with a missense variant in RLIM

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