A Mutant Form of MeCP2 Protein Associated with Human Rett Syndrome Cannot Be Displaced from Methylated DNA by Notch in Xenopus Embryos

Stancheva, Irina; Collins, Anne L.; Veyver, Ingatia B. Van den; Zoghbi, Huda Y.; Meehan, Richard R.

doi:10.1016/j.molcel.2016.06.007

Cited by 46 publications

(9 citation statements)

References 34 publications

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“…1) was mapped in experiments involving recruitment of MeCP2 fragments to a reporter gene using a heterologous DNA-binding module 72 . Moreover, MeCP2 has been reported to interact with the histone deacetylase (HDAC)-containing co-repressor complexes SIN3A 73,74 , NCOR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoic acid and thyroid hormone receptor; also known as NCOR2) 75,76 . Although the SIN3A-binding site on MeCP2 has not been precisely defined, the NCOR-SMRT interaction domain (NID) (FIG.…”

Section: Mecp2 Regulates Gene Expressionmentioning

confidence: 99%

Rett syndrome: a complex disorder with simple roots

2015

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Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the X-linked gene MECP2 (methyl-CpG-binding protein 2). Two decades of research have fostered the view that MeCP2 is a multifunctional chromatin protein that integrates diverse aspects of neuronal biology. More recently, studies have focused on specific RTT-associated mutations within the protein. This work has yielded molecular insights into the critical functions of MeCP2 that promise to simplify our understanding of RTT pathology.

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Section: Mecp2 Regulates Gene Expressionmentioning

confidence: 99%

Rett syndrome: a complex disorder with simple roots

2015

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“…MeCP2 is also known to bind the co-repressors SMRT (silencing mediator for retinoid and thyroid receptors) [72], c-Ski (first isolated at Sloan Kettering Institute) and N-CoR (nuclear receptor corepressor 1) [69], which appear to be in complexes that do not include the Sin3 co-repressor [69]. Interestingly, some MeCP2 RTT mutations interfere with these interactions.…”

Section: Mecp2 Interacts With Multiple Partnersmentioning

confidence: 99%

MECP2, a multi-talented modulator of chromatin architecture

Ragione

Vacca²,

Fioriniello³

et al. 2016

Briefings in Functional Genomics

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It has been a long trip from 1992, the year of the discovery of MECP2, to the present day. What is surprising is that some of the pivotal roles of MeCP2 were already postulated at that time, such as repression of inappropriate expression from repetitive elements and the regulation of pericentric heterochromatin condensation. However, MeCP2 performs many more functions. MeCP2 is a reader of epigenetic information contained in methylated (and hydroxymethylated) DNA, moving from the 'classical' CpG doublet to the more complex view addressed by the non-CpG methylation, which is a feature of the postnatal brain. MECP2 is a transcriptional repressor, although when it forms complexes with the appropriate molecules, it can become a transcriptional activator. For all of these aspects, Rett syndrome, which is caused by MECP2 mutations, is considered a paradigmatic example of a 'chromatin disorder'. Even if the hunt for bona-fide MECP2 target genes is far from concluded today, the role of MeCP2 in the maintenance of chromatin architecture appears to be clearly established. Taking a cue from the non-scientific literature, we can firmly attest that MeCP2 is a player with 'a great future behind it'*.*V. Gassmann 'Un grande avvenire dietro le spalle'. TEA Eds.

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“…RTT is a disorder of known genetic etiology, with the vast majority of cases the result of de novo mutations in the methyl-CpG-binding protein 2 (MECP2) gene (2). MeCP2 binds preferentially to symmetrically methylated CpG dinucleotides via its methyl-CpG-binding domain (MBD) and is thought to mediate transcriptional repression through the recruitment of corepressors, such as the SIN3 transcription regulator family member A (SIN3A) and the nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressor complexes (3)(4)(5)(6)(7). Recent studies, however, have revealed that MeCP2-dependent gene regulation is much more complex, with MeCP2 activating or repressing gene expression depending on the cellular context, gene length, and signatures of DNA methylation (8)(9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Elevating expression of MeCP2 T158M rescues DNA binding and Rett syndrome–like phenotypes

Lamonica¹,

Kwon²,

Goffin³

et al. 2017

Journal of Clinical Investigation

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Mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome (RTT), a neurological disorder affecting cognitive development, respiration, and motor function. Genetic restoration of MeCP2 expression reverses RTT-like phenotypes in mice, highlighting the need to search for therapeutic approaches. Here, we have developed knockin mice recapitulating the most common RTT-associated missense mutation, MeCP2 T158M. We found that the T158M mutation impaired MECP2 binding to methylated DNA and destabilized MeCP2 protein in an age-dependent manner, leading to the development of RTT-like phenotypes in these mice. Genetic elevation of MeCP2 T158M expression ameliorated multiple RTT-like features, including motor dysfunction and breathing irregularities, in both male and female mice. These improvements were accompanied by increased binding of MeCP2 T158M to DNA. Further, we found that the ubiquitin/proteasome pathway was responsible for MeCP2 T158M degradation and that proteasome inhibition increased MeCP2 T158M levels. Together, these findings demonstrate that increasing MeCP2 T158M protein expression is sufficient to mitigate RTT-like phenotypes and support the targeting of MeCP2 T158M expression or stability as an alternative therapeutic approach.

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A Mutant Form of MeCP2 Protein Associated with Human Rett Syndrome Cannot Be Displaced from Methylated DNA by Notch in Xenopus Embryos

Cited by 46 publications

References 34 publications

Rett syndrome: a complex disorder with simple roots

Rett syndrome: a complex disorder with simple roots

MECP2, a multi-talented modulator of chromatin architecture

Elevating expression of MeCP2 T158M rescues DNA binding and Rett syndrome–like phenotypes

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