scholarly journals Binding of the Rett syndrome protein, MeCP2, to methylated and unmethylated DNA and chromatin

IUBMB Life ◽  
2010 ◽  
Vol 62 (10) ◽  
pp. 732-738 ◽  
Author(s):  
Jeffrey C. Hansen ◽  
Rajarshi P. Ghosh ◽  
Christopher L. Woodcock
Keyword(s):  
Rett Syndrome ◽  
Syndrome Protein ◽  
Protein Mecp2

scholarly journals The Rett Syndrome Protein MeCP2 Regulates Synaptic Scaling

2012 ◽  
Vol 32 (3) ◽  
pp. 989-994 ◽  
Author(s):  
Z. Qiu ◽  
E. L. Sylwestrak ◽  
D. N. Lieberman ◽  
Y. Zhang ◽  
X.-Y. Liu ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Synaptic Scaling ◽  
Syndrome Protein ◽  
Protein Mecp2

scholarly journals Rett syndrome protein MeCP2 regulates critical period plasticity of visual cortex

2016 ◽  
Vol 10 ◽  
Author(s):  
He Ling-jie He ◽  
Liu Nan ◽  
Chen Xiao-jing ◽  
Li Yi-ding ◽  
Zhang Xiaohui
Keyword(s):  
Visual Cortex ◽  
Rett Syndrome ◽  
Critical Period ◽  
Syndrome Protein ◽  
Protein Mecp2

MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion

Science ◽  
2021 ◽  
Vol 372 (6549) ◽  
pp. eabd5581 ◽  
Author(s):  
Abdulkhaleg Ibrahim ◽  
Christophe Papin ◽  
Kareem Mohideen-Abdul ◽  
Stéphanie Le Gras ◽  
Isabelle Stoll ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Binding Protein ◽  
Dna Binding Protein ◽  
Ca Repeat ◽  
Transcriptional Dysregulation ◽  
Genome Wide ◽  
Exact Function ◽  
Dna Shape ◽  
Syndrome Protein ◽  
Protein Mecp2

The Rett syndrome protein MeCP2 was described as a methyl-CpG-binding protein, but its exact function remains unknown. Here we show that mouse MeCP2 is a microsatellite binding protein that specifically recognizes hydroxymethylated CA repeats. Depletion of MeCP2 alters chromatin organization of CA repeats and lamina-associated domains and results in nucleosome accumulation on CA repeats and genome-wide transcriptional dysregulation. The structure of MeCP2 in complex with a hydroxymethylated CA repeat reveals a characteristic DNA shape, with considerably modified geometry at the 5-hydroxymethylcytosine, which is recognized specifically by Arg133, a key residue whose mutation causes Rett syndrome. Our work identifies MeCP2 as a microsatellite DNA binding protein that targets the 5hmC-modified CA-rich strand and maintains genome regions nucleosome-free, suggesting a role for MeCP2 dysfunction in Rett syndrome.

scholarly journals DNMT3A haploinsufficiency results in behavioral deficits and global epigenomic dysregulation shared across neurodevelopmental disorders

2020 ◽  
Author(s):  
Diana L. Christian ◽  
Dennis Y. Wu ◽  
Jenna R. Martin ◽  
J. Russell Moore ◽  
Yiran R. Liu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Rett Syndrome ◽  
Neurodevelopmental Disorders ◽  
Dna Methyltransferase ◽  
Behavioral Alterations ◽  
Protein Activity ◽  
Neurodevelopmental Disease ◽  
Convergence Point ◽  
Nervous System Function ◽  
Syndrome Protein

SummaryMutations in DNA methyltransferase 3A (DNMT3A) have been detected in autism and related disorders, but how these mutations disrupt nervous system function is unknown. Here we define the effects of neurodevelopmental disease-associated DNMT3A mutations. We show that diverse mutations affect different aspects of protein activity yet lead to shared deficiencies in neuronal DNA methylation. Heterozygous DNMT3A knockout mice mimicking DNMT3A disruption in disease display growth and behavioral alterations consistent with human phenotypes. Strikingly, in these mice we detect global disruption of neuron-enriched non-CG DNA methylation, a binding site for the Rett syndrome protein MeCP2. Loss of this methylation leads to enhancer and gene dysregulation that overlaps with models of Rett syndrome and autism. These findings define effects of DNMT3A haploinsufficiency in the brain and uncover disruption of the non-CG methylation pathway as a convergence point across neurodevelopmental disorders.

scholarly journals The role of N-terminal modification of MeCP2 in the pathophysiology of Rett syndrome

2017 ◽  
Author(s):  
Taimoor I. Sheikh ◽  
Alexia Martínez de Paz ◽  
Shamim Akhtar ◽  
Juan Ausió ◽  
John B. Vincent
Keyword(s):  
Missense Mutation ◽  
Rett Syndrome ◽  
Degradation Rate ◽  
Regulatory Protein ◽  
Translational Efficiency ◽  
Disease Genes ◽  
Degradation Rates ◽  
Exon 1 ◽  
Syndrome Protein

AbstractMethyl CpG-binding protein 2 (MeCP2), the mutated protein in Rett syndrome (RTT), is a crucial chromatin-modifying and gene-regulatory protein that has two main isoforms (MeCP2_E1 and MeCP2_ E2) due to the alternative splicing and switching between translation start codons in exons one and two. Functionally, these two isoforms appear to be virtually identical; however, evidence suggests that only MeCP2_E1 is relevant to RTT, including a single RTT missense mutation in exon 1, p.Ala2Val. Here, we show that N-terminal co- and post- translational modifications differ for MeCP2_E1, MeCP2_E1-p.Ala2Val and MeCP2_E2, which result in different protein degradation rates in vitro. We report partial N-methionine excision (NME) for MeCP2_E2, whereas NME for MeCP2_E1 is complete. Surprisingly, we also observed evidence of excision of multiple alanine residues from the N-terminal polyalanine stretch. Regarding MeCP2_E1-Ala2Val, we also observed only partial NME and N-acetylation (NA) of either methionine or valine. The localization of MeCP2_E1 and co-localization with chromatin appear to be unaffected by the p.Ala2Val mutation. However, a higher proteasomal degradation rate was observed for MeCP2_E1-Ala2Val compared with that for wild type (WT) MeCP2_E1. Thus, the etiopathology of p.Ala2Val is likely due to a reduced bio-availability of MeCP2 because of the faster degradation rate of the unmodified defective protein. MeCP2_E1 is thought to have a much higher translational efficiency than MeCP2_E2. Our data suggest that this increased efficiency may be balanced by a higher degradation rate. The higher turnover rate of the MeCP2_E1 protein suggests that it may play a more dynamic role in cells than MeCP2_E2.Significance statementThe Rett syndrome protein, MeCP2, undergoes a number of modifications before becoming functionally active in the body’s cells. Here, we report the presence of N-terminal modifications in both MeCP2 isoforms, MeCP2_E1 and MeCP2_E2, and that the only reported Rett missense mutation in exon 1, p.Ala2Val, disrupts these modifications, decreasing the longevity of the protein. Interestingly, p.Ala2Val mutations have been reported in many other disease genes, such as DKCX, ECHS1, IRF6, SMN1, and TNNI3, and the etiopathological mechanism(s) have never been explained. Thus, this work is important not only for the understanding of the pathophysiology of Rett syndrome but also for a deeper understanding of the effects of genetic mutations at the N-terminal end of genes in general.

The methyl-CpG-binding protein MeCP2 and neurological disease

2008 ◽  
Vol 36 (4) ◽  
pp. 575-583 ◽  
Author(s):  
Adrian Bird
Keyword(s):  
Dna Methylation ◽  
Rett Syndrome ◽  
Dna Sequences ◽  
Neurological Disease ◽  
Binding Protein ◽  
Autism Spectrum ◽  
Model Systems ◽  
Mecp2 Gene ◽  
Methylated Dna ◽  
Protein Mecp2

The methyl-CpG-binding protein MeCP2 was discovered over 15 years ago as part of a search for proteins that selectively bind methylated DNA. It is a nuclear protein that is largely chromatin-bound and has a strong preference for binding to methylated DNA sequences in vivo. Evidence from model systems shows that MeCP2 can recruit the Sin3a co-repressor complex to promoters leading to transcriptional repression, therefore suggesting that MeCP2 can interpret the DNA methylation signal to bring about gene silencing. Mutations in the human MECP2 gene cause the autism spectrum disorder Rett Syndrome. MeCP2 is most highly expressed in neurons, and mice lacking this protein show symptoms that strikingly parallel those of Rett patients. Surprisingly, these symptoms are efficiently reversed by delayed activation of a ‘stopped’ Mecp2 gene, raising hopes that human Rett syndrome may also be reversible. Future studies of MeCP2 promise to shed light upon brain function, neurological disease and the biology of DNA methylation.

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