Testing the PEST hypothesis using relevant Rett mutations in MeCP2 E1 and E2 isoforms

Mutations in methyl-CpG binding protein 2 (MeCP2), such as the T158M, P152R, R294X, and R306C mutations, are responsible for most Rett syndrome (RTT) cases. These mutations often result in altered protein expression that appears to correlate with changes in the nuclear size; however, the molecular details of these observations are poorly understood. Using a C2C12 cellular system expressing human MeCP2-E1 isoform as well as mouse models expressing these mutations, we show that T158M and P152R result in a decrease in MeCP2 protein, whereas R306C has a milder variation, and R294X resulted in an overall 2.5 to 3 fold increase. We also explored the potential involvement of the MeCP2 PEST domains in the proteasome-mediated regulation of MeCP2. Finally, we used the R294X mutant to gain further insight into the controversial competition between MeCP2 and histone H1 in the chromatin context. Interestingly, in R294X, MeCP2 E1 and E2 isoforms were differently affected, where the E1 isoform contributes to much of the overall protein increase observed, while E2 decreases by half. The modes of MeCP2 regulation, thus, appear to be differently regulated in the two isoforms.

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Publication Details

Journal
Human Molecular Genetics
Published
2024-08-13
DOI
https://doi.org/10.1093/hmg/ddae119
Citations
1
Primary Topic
Genetics and Neurodevelopmental Disorders
Type
article
Field-Weighted Citation Impact
0.55

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article

Testing the PEST hypothesis using relevant Rett mutations in MeCP2 E1 and E2 isoforms

Juan Ausió, Robert L. Chow, Anastasia Roemer, Zhaolan Zhou et al.
1 citations
Human Molecular Genetics
Genetics and Neurodevelopmental Disorders
0.55
article

Testing the PEST hypothesis using relevant Rett mutations in MeCP2 E1 and E2 isoforms

Juan Ausió, Robert L. Chow, Anastasia Roemer, Zhaolan Zhou, Jeffrey L. Neul, John B. Vincent, Jonathan K. Merritt, Kerry R. Delaney, Michael J. Hendzel, Katrina Good, Ladan Kalani, Bo‐Hyun Kim, Anna Mikhailov, Alberto Ruiz de Chavez
article en
1 citations

Abstract

Mutations in methyl-CpG binding protein 2 (MeCP2), such as the T158M, P152R, R294X, and R306C mutations, are responsible for most Rett syndrome (RTT) cases. These mutations often result in altered protein expression that appears to correlate with changes in the nuclear size; however, the molecular details of these observations are poorly understood. Using a C2C12 cellular system expressing human MeCP2-E1 isoform as well as mouse models expressing these mutations, we show that T158M and P152R result in a decrease in MeCP2 protein, whereas R306C has a milder variation, and R294X resulted in an overall 2.5 to 3 fold increase. We also explored the potential involvement of the MeCP2 PEST domains in the proteasome-mediated regulation of MeCP2. Finally, we used the R294X mutant to gain further insight into the controversial competition between MeCP2 and histone H1 in the chromatin context. Interestingly, in R294X, MeCP2 E1 and E2 isoforms were differently affected, where the E1 isoform contributes to much of the overall protein increase observed, while E2 decreases by half. The modes of MeCP2 regulation, thus, appear to be differently regulated in the two isoforms.

Human Molecular GeneticsVol. 33(21)
Centre for Addiction and Mental Health (CA), University of Alberta (CA), University of Toronto (CA), University of Victoria (CA), Canada Research Chairs (CA), Institute of Human Genetics (PL), University of Pennsylvania (US), Vanderbilt University Medical Center (US)
University of Pennsylvania, Perelman School of Medicine, University of Pennsylvania
Openalex Percentile: Top 27%
Genetics and Neurodevelopmental Disorders
0.55
DOIOpen Access PDFOpenAlex
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