MeCP2 nuclear dynamics in live neurons results from low and high affinity chromatin interactions

• Published in: eLife Vol. 8
• Main Authors: Piccolo, Francesco M, Liu, Zhe, Dong, Peng, Hsu, Ching-Lung, Stoyanova, Elitsa I, Rao, Anjana, Tjian, Robert, Heintz, Nathaniel
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 23-12-2019; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Affinity; Chromatin; CpG islands; Deoxyribonucleic acid; DNA; DNA binding proteins; DNA methylation; Gene expression; Genes; Genomes; Histones; Lasers; Ligands; live imaging of neurons; MeCP2; MeCP2 protein; Methyl-CpG binding protein; Mutation; Neurons; Neuroscience; nuclear diffusion; Protein binding; Proteins; single molecule tracking; Standard deviation; Structural Biology and Molecular Biophysics; Transcription factors; MeCP2; mouse; live imaging of neurons; neuroscience; nuclear diffusion; structural biology; molecular biophysics; single molecule tracking
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.51449

Methyl-CpG-binding-Protein 2 (MeCP2) is an abundant nuclear protein highly enriched in neurons. Here we report live-cell single-molecule imaging studies of the kinetic features of mouse MeCP2 at high spatial-temporal resolution. MeCP2 displays dynamic features that are distinct from both highly mobile transcription factors and immobile histones. Stable binding of MeCP2 in living neurons requires its methyl-binding domain and is sensitive to DNA modification levels. Diffusion of unbound MeCP2 is strongly constrained by weak, transient interactions mediated primarily by its AT-hook domains, and varies with the level of chromatin compaction and cell type. These findings extend previous studies of the role of the MeCP2 MBD in high affinity DNA binding to living neurons, and identify a new role for its AT-hooks domains as critical determinants of its kinetic behavior. They suggest that limited nuclear diffusion of MeCP2 in live neurons contributes to its local impact on chromatin structure and gene expression.