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MeCP2 Binding Cooperativity Inhibits DNA Modification-Specific Recognition.

ABSTRACT: Methyl-CpG binding protein 2 (MeCP2) is a multifunctional protein that guides neuronal development through its binding to DNA, recognition of sites of methyl-CpG (mCpG) DNA modification, and interaction with other regulatory proteins. Our study explores the relationship between mCpG and hydroxymethyl-CpG (hmCpG) recognition mediated by its mCpG binding domain (MBD) and binding cooperativity mediated by its C-terminal polypeptide. Previous study of the isolated MBD of MeCP2 documented an unusual mechanism by which ion uptake is required for discrimination of mCpG and hmCpG from CpG. MeCP2 binding cooperativity suppresses discrimination of modified DNA and is highly sensitive to both the total ion concentration and the type of counterions. Higher than physiological total ion concentrations completely suppress MeCP2 binding cooperativity, indicating a dominant electrostatic component to the interaction. Substitution of SO4(2-) for Cl(-) at physiological total ion concentrations also suppresses MeCP2 binding cooperativity, This effect is of particular note as the intracellular Cl(-) concentration changes during neuronal development. A related effect is that the protein-stabilizing solutes, TMAO and glutamate, reduce MeCP2 (but not isolated MBD) binding affinity by 2 orders of magnitude without affecting the apparent binding cooperativity. These observations suggest that polypeptide flexibility facilitates DNA binding by MeCP2. Consistent with this view, nuclear magnetic resonance (NMR) analyses show that ions have discrete effects on the structure of MeCP2, both MBD and the C-terminal domains. Notably, anion substitution results in changes in the NMR chemical shifts of residues, including some whose mutation causes the autism spectrum disorder Rett syndrome. Binding cooperativity makes MeCP2 an effective competitor with histone H1 for accessible DNA sites. The relationship between MeCP2 binding specificity and cooperativity is discussed in the context of chromatin binding, neuronal function, and neuronal development.

SUBMITTER: Khrapunov S

PROVIDER: S-EPMC6532394 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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MeCP2 Binding Cooperativity Inhibits DNA Modification-Specific Recognition.

Khrapunov Sergei S Tao Yisong Y Cheng Huiyong H Padlan Camille C Harris Richard R Galanopoulou Aristea S AS Greally John M JM Girvin Mark E ME Brenowitz Michael M

Biochemistry 20160728 31

Methyl-CpG binding protein 2 (MeCP2) is a multifunctional protein that guides neuronal development through its binding to DNA, recognition of sites of methyl-CpG (mCpG) DNA modification, and interaction with other regulatory proteins. Our study explores the relationship between mCpG and hydroxymethyl-CpG (hmCpG) recognition mediated by its mCpG binding domain (MBD) and binding cooperativity mediated by its C-terminal polypeptide. Previous study of the isolated MBD of MeCP2 documented an unusual ...[more]

PMID: 27420643

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Project description:MeCP2 is a critical epigenetic regulator in brain and its abnormal expression or compromised function leads to a spectrum of neurological disorders including Rett Syndrome and autism. Altered expression of the two MeCP2 isoforms, MeCP2E1 and MeCP2E2 has been implicated in neurological complications. However, expression, regulation and functions of the two isoforms are largely uncharacterized. Previously, we showed the role of MeCP2E1 in neuronal maturation and reported MeCP2E1 as the major protein isoform in the adult mouse brain, embryonic neurons and astrocytes. Recently, we showed that DNA methylation at the regulatory elements (REs) within the Mecp2 promoter and intron 1 impact the expression of Mecp2 isoforms in differentiating neural stem cells. This current study is aimed for a comparative analysis of temporal, regional and cell type-specific expression of MeCP2 isoforms in the developing and adult mouse brain. MeCP2E2 displayed a later expression onset than MeCP2E1 during mouse brain development. In the adult female and male brain hippocampus, both MeCP2 isoforms were detected in neurons, astrocytes and oligodendrocytes. Furthermore, MeCP2E1 expression was relatively uniform in different brain regions (olfactory bulb, striatum, cortex, hippocampus, thalamus, brainstem and cerebellum), whereas MeCP2E2 showed differential enrichment in these brain regions. Both MeCP2 isoforms showed relatively similar distribution in these brain regions, except for cerebellum. Lastly, a preferential correlation was observed between DNA methylation at specific CpG dinucleotides within the REs and Mecp2 isoform-specific expression in these brain regions. Taken together, we show that MeCP2 isoforms display differential expression patterns during brain development and in adult mouse brain regions. DNA methylation patterns at the Mecp2 REs may impact this differential expression of Mecp2/MeCP2 isoforms in brain regions. Our results significantly contribute towards characterizing the expression profiles of Mecp2/MeCP2 isoforms and thereby provide insights on the potential role of MeCP2 isoforms in the developing and adult brain.

Dataset Information

MeCP2 Binding Cooperativity Inhibits DNA Modification-Specific Recognition.

Publications

MeCP2 Binding Cooperativity Inhibits DNA Modification-Specific Recognition.

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