RNF12 Is an X-Encoded Dose-Dependent Activator of X Chromosome Inactivation

Jonkers, Iris; Barakat, Tahsin Stefan; Mulugeta, Eskeatnaf; Monkhorst, Kim; Kenter, Annegien; Rentmeester, Eveline; Grosveld, Frank; Grootegoed, J. Anton; Gribnau, Joost

doi:10.1016/j.cell.2009.10.034

Cited by 219 publications

(295 citation statements)

References 34 publications

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“…S7 C and E), suggesting a crucial role of Rnf12 transcription in the expression of Xist during preimplantation stage. In addition, RNF12 can specifically activate Xist expression in the paternal X chromosome during iXCI and also prevent excessive up-regulation of Xist with a rapid feedback mechanism (24,33). Together, these data show that Rnf12 overexpression can be used to compensate impaired iXCI by fine-tuning Xist expression in IVF female embryos.…”

Section: Resultsmentioning

confidence: 70%

Impaired imprinted X chromosome inactivation is responsible for the skewed sex ratio following in vitro fertilization

Tan

Kai

et al. 2016

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

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Dynamic epigenetic reprogramming occurs during normal embryonic development at the preimplantation stage. Erroneous epigenetic modifications due to environmental perturbations such as manipulation and culture of embryos during in vitro fertilization (IVF) are linked to various short-or long-term consequences. Among these, the skewed sex ratio, an indicator of reproductive hazards, was reported in bovine and porcine embryos and even human IVF newborns. However, since the first case of sex skewing reported in 1991, the underlying mechanisms remain unclear. We reported herein that sex ratio is skewed in mouse IVF offspring, and this was a result of female-biased peri-implantation developmental defects that were originated from impaired imprinted X chromosome inactivation (iXCI) through reduced ring finger protein 12 (Rnf12)/X-inactive specific transcript (Xist) expression. Compensation of impaired iXCI by overexpression of Rnf12 to up-regulate Xist significantly rescued femalebiased developmental defects and corrected sex ratio in IVF offspring. Moreover, supplementation of an epigenetic modulator retinoic acid in embryo culture medium up-regulated Rnf12/Xist expression, improved iXCI, and successfully redeemed the skewed sex ratio to nearly 50% in mouse IVF offspring. Thus, our data show that iXCI is one of the major epigenetic barriers for the developmental competence of female embryos during preimplantation stage, and targeting erroneous epigenetic modifications may provide a potential approach for preventing IVF-associated complications.in vitro fertilization | sex ratio | X chromosome inactivation | Xist | Rnf12

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Section: Resultsmentioning

confidence: 70%

Impaired imprinted X chromosome inactivation is responsible for the skewed sex ratio following in vitro fertilization

Tan

Kai

et al. 2016

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

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“…51 RNAi mediated knockdown of Scc3/SA protein levels can also result in altered transcription of cohesinregulated genes, perhaps by altering cohesin's insulator function. 52 Similarly to the finding that protein levels of X-linked genes can be critical for the regulation of XCI, 53 precise SA2 expression levels could be important for XCI choice.…”

Section: Discussionmentioning

confidence: 94%

Familial skewed X-chromosome inactivation linked to a component of the cohesin complex, SA2

et al. 2011

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The gene dosage inequality between females with two X-chromosomes and males with one is compensated for by X-chromosome inactivation (XCI), which ensures the silencing of one X in every somatic cell of female mammals. XCI in humans results in a mosaic of two cell populations: those expressing the maternal X-chromosome and those expressing the paternal X-chromosome. We have previously shown that the degree of mosaicism (the X-inactivation pattern) in a Canadian family is directly related to disease severity in female carriers of the X-linked recessive bleeding disorder, haemophilia A. The distribution of X-inactivation patterns in this family was consistent with a genetic trait having a co-dominant mode of inheritance, suggesting that XCI choice may not be completely random. To identify genetic elements that could be responsible for biased XCI choice, a linkage analysis was undertaken using an approach tailored to accommodate the continuous nature of the X-inactivation pattern phenotype in the Canadian family. Several X-linked regions were identified, one of which overlaps with a region previously found to be linked to familial skewed XCI. SA2, a component of the cohesin complex is identified as a candidate gene that could participate in XCI through its association with CTCF.

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“…The involvement of Rnf12 in maintenance of XCI via the BMP/TGF-β pathway is particularly intriguing, because Rnf12 has a known role in initiation of XCI that is independent of TGF-β: During ES cell differentiation, Rnf12 induces XIST expression by promoting ubiquitylation and degradation of REX1, a pluripotency factor that represses XIST transcription in ES cells (14). Whereas REX1 is no longer expressed in differentiated cells, our results indicate that Rnf12 has retained its role as an XIST activator in differentiated cells through augmentation of BMP signaling.…”

Section: Discussionmentioning

confidence: 99%

“…We found that the BMP signaling pathway is required for maintenance of XIST expression. Furthermore, we show that Rnf12, a known regulator of BMP signaling (13), modulates XIST expression in adult cells, suggesting that the role of Rnf12 as a regulator of XIST during initiation of X-chromosome inactivation in ES cells (14,15) is retained in differentiated cells through control of BMP signaling.…”

mentioning

confidence: 96%

Screen for reactivation of MeCP2 on the inactive X chromosome identifies the BMP/TGF-β superfamily as a regulator of XIST expression

Sripathy

Leko

Adrianse

et al. 2017

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

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Rett syndrome (RS) is a debilitating neurological disorder affecting mostly girls with heterozygous mutations in the gene encoding the methyl-CpG-binding protein MeCP2 on the X chromosome. Because restoration of MeCP2 expression in a mouse model reverses neurologic deficits in adult animals, reactivation of the wild-type copy of MeCP2 on the inactive X chromosome (Xi) presents a therapeutic opportunity in RS. To identify genes involved in MeCP2 silencing, we screened a library of 60,000 shRNAs using a cell line with a MeCP2 reporter on the Xi and found 30 genes clustered in seven functional groups. More than half encoded proteins with known enzymatic activity, and six were members of the bone morphogenetic protein (BMP)/TGF-β pathway. shRNAs directed against each of these six genes down-regulated X-inactive specific transcript (XIST), a key player in X-chromosome inactivation that encodes an RNA that coats the silent X chromosome, and modulation of regulators of this pathway both in cell culture and in mice demonstrated robust regulation of XIST. Moreover, we show that Rnf12, an X-encoded ubiquitin ligase important for initiation of X-chromosome inactivation and XIST transcription in ES cells, also plays a role in maintenance of the inactive state through regulation of BMP/TGF-β signaling. Our results identify pharmacologically suitable targets for reactivation of MeCP2 on the Xi and a genetic circuitry that maintains XIST expression and X-chromosome inactivation in differentiated cells.XIST | X inactivation | MeCP2 | Rett syndrome | BMP/TGF-β

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RNF12 Is an X-Encoded Dose-Dependent Activator of X Chromosome Inactivation

Cited by 219 publications

References 34 publications

Impaired imprinted X chromosome inactivation is responsible for the skewed sex ratio following in vitro fertilization

Impaired imprinted X chromosome inactivation is responsible for the skewed sex ratio following in vitro fertilization

Familial skewed X-chromosome inactivation linked to a component of the cohesin complex, SA2

Screen for reactivation of MeCP2 on the inactive X chromosome identifies the BMP/TGF-β superfamily as a regulator of XIST expression

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