Binding of MBD proteins to DNA blocks Tet1 function thereby modulating transcriptional noise

Ludwig, Anne K.; Zhang, Peng; Hastert, Florian D.; Meyer, Steven De; Rausch, Cathia; Herce, Henry D.; Müller, Udo; Lehmkuhl, Anne; Hellmann, Ines; Trummer, Carina; Storm, Christian; Leonhardt, Heinrich; Cardoso, M. Cristina

doi:10.1093/nar/gkw1197

Cited by 40 publications

(46 citation statements)

References 77 publications

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“…To assess the binding dynamics between MM2-EGFP and heterochromatin, we performed transient transfection followed by Fluorescence Recovery After Photobleaching (FRAP). WT-EGFP binding recovered at heterochromatic foci with a half-life of 34.7 ± 2.3 s ( Figure 2F), consistent with previous studies (Ghosh et al, 2010;Klose et al, 2005;Ludwig et al, 2017).…”

Section: A Chimeric Mecp2 That Selectively Binds Mcgsupporting

confidence: 91%

Neuronal non-CG methylation is an essential target for MeCP2 function

Tillotson

Cholewa-Waclaw

Chhatbar

et al. 2020

Preprint

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SUMMARYDNA methylation is implicated in neuronal biology via the protein MeCP2, mutation of which causes Rett syndrome. MeCP2 recruits the NCOR1/2 corepressor complexes to methylated cytosine in the CG dinucleotide, but also to non-CG methylation, which is abundant specifically in neuronal genomes. To test the biological significance of its dual binding specificity, we replaced the MeCP2 DNA binding domain with an orthologous domain whose specificity is restricted to mCG motifs. Knock-in mice expressing the domain-swap protein displayed severe Rett syndrome-like phenotypes, demonstrating that interaction with sites of non-CG methylation, specifically the mCAC trinucleotide, is critical for normal brain function. The results support the notion that the delayed onset of Rett syndrome is due to the late accumulation of both mCAC and its reader MeCP2. Intriguingly, genes dysregulated in both Mecp2-null and domain-swap mice are implicated in other neurological disorders, potentially highlighting targets of particular relevance to the Rett syndrome phenotype.

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Section: A Chimeric Mecp2 That Selectively Binds Mcgsupporting

confidence: 91%

Neuronal non-CG methylation is an essential target for MeCP2 function

Tillotson

Cholewa-Waclaw

Chhatbar

et al. 2020

Preprint

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“…An dditional factor, that may play a role in MeCP2 binding is phosphorylation. Alternatively, additional methyl domain containing proteins, such as MBD2, bind to MECP2, and restrict access of other proteins like TET1 to the promoter DNA (Ludwig et al, 2016). Other factors such as neuron‐restrictive silencing factor (REST), may play a role in determining the binding specificity of MECP2 in neurons and non‐neuronal cells (Zhao et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic regulation of RELN and GAD1 in the frontal cortex (FC) of autism spectrum disorder (ASD) subjects

Zhubi

Chen

Guidotti

et al. 2017

Intl J of Devlp Neuroscience

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Both Reelin (RELN) and glutamate decarboxylase 67 (GAD1) have been implicated in the pathophysiology of Autism Spectrum Disorders (ASD). We have previously shown that both mRNAs are reduced in the cerebella (CB) of ASD subjects through a mechanism that involves increases in the amounts of MECP2 binding to the corresponding promoters. In the current study, we examined the expression of RELN, GAD1, GAD2, and several other mRNAs implicated in this disorder in the frontal cortices (FC) of ASD and CON subjects. We also focused on the role that epigenetic processes play in the regulation of these genes in ASD brain. Our goal is to better understand the molecular basis for the down-regulation of genes expressed in GABAergic neurons in ASD brains. We measured mRNA levels corresponding to selected GABAergic genes using qRT-PCR in RNA isolated from both ASD and CON groups. We determined the extent of binding of MECP2 and DNMT1 repressor proteins by chromatin immunoprecipitation (ChIP) assays. The amount of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) present in the promoters of the target genes was quantified by methyl DNA immunoprecipitation (MeDIP) and hydroxyl MeDIP (hMeDIP). We detected significant reductions in the mRNAs associated with RELN and GAD1 and significant increases in mRNAs encoding the Ten-eleven Translocation (TET) enzymes 1, 2, and 3. We also detected increased MECP2 and DNMT1 binding to the corresponding promoter regions of GAD1, RELN, and GAD2. Interestingly, there was decreased amounts of 5mC at both promoters and little change in 5hmC content in these same DNA fragments. Our data demonstrate that RELN, GAD1, and several other genes selectively expressed in GABAergic neurons, are down-regulated in post-mortem ASD FC. In addition, we observed increased DNMT1 and MECP2 binding at the corresponding promoters of these genes. The finding of increased MECP2 binding to the RELN, GAD1 and GAD2 promoters, with reduced amounts of 5mC and unchanged amounts of 5hmC present in these regions, suggests the possibility that DNMT1 interacts with and alters MECP2 binding properties to selected promoters. Comparisons between data obtained from the FC with CB studies showed some common themes between brain regions which are discussed.

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“…Eventually, we reinforced these data analyzing whether WT, Mecp2-null and Mecp2 Y120D/y mature brain cortices (P40) differ in their 5-hydromethylcytosine (5-hmC) content. In fact, a direct relationship between genome accessibility, transcriptional activity and 5-hmC levels has recently been proposed [36,37]. In particular, methylated CG dinucleotides contained in highly compact chromatin are less frequently converted to 5-hmC, probably because of lower accessibility of Tet hydroxylases [36].…”

Section: Mecp2 Y120d and Mecp2-null Brains Exhibit Different Chromatimentioning

confidence: 99%

A Novel Mecp2Y120D Knock-in Model Displays Similar Behavioral Traits But Distinct Molecular Features Compared to the Mecp2-Null Mouse Implying Precision Medicine for the Treatment of Rett Syndrome

et al. 2018

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We are extremely grateful to Giovanni Tonon and Simona Segalla (San Raffaele Scientific Institute) for their helpful technical suggestions. This work was mainly supported by the Italian parents' association "pro RETT ricerca" to N.L. The financial support of Fondazione Telethon-Italy [Grant no. GGP16015 to F.A.] is gratefully acknowledged. Functional experiments were supported by the Italian Ministry of Research and Education program "FIRB giovani" 2010, protocol number: RBFR10ZBYZ.

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Binding of MBD proteins to DNA blocks Tet1 function thereby modulating transcriptional noise

Cited by 40 publications

References 77 publications

Neuronal non-CG methylation is an essential target for MeCP2 function

Neuronal non-CG methylation is an essential target for MeCP2 function

Epigenetic regulation of RELN and GAD1 in the frontal cortex (FC) of autism spectrum disorder (ASD) subjects

A Novel Mecp2Y120D Knock-in Model Displays Similar Behavioral Traits But Distinct Molecular Features Compared to the Mecp2-Null Mouse Implying Precision Medicine for the Treatment of Rett Syndrome

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