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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.<\/jats:p>","DOI":"10.7554\/elife.51449","type":"journal-article","created":{"date-parts":[[2019,12,23]],"date-time":"2019-12-23T08:01:38Z","timestamp":1577088098000},"source":"Crossref","is-referenced-by-count":43,"title":["MeCP2 nuclear dynamics in live neurons results from low and high affinity chromatin interactions"],"prefix":"10.7554","volume":"8","author":[{"given":"Francesco M","family":"Piccolo","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3592-3150","authenticated-orcid":true,"given":"Zhe","family":"Liu","sequence":"additional","affiliation":[{"name":"Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng","family":"Dong","sequence":"additional","affiliation":[{"name":"Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ching-Lung","family":"Hsu","sequence":"additional","affiliation":[{"name":"Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6400-6119","authenticated-orcid":true,"given":"Elitsa I","family":"Stoyanova","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anjana","family":"Rao","sequence":"additional","affiliation":[{"name":"La Jolla Institute for Allergy and Immunology, La Jolla, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0539-8217","authenticated-orcid":true,"given":"Robert","family":"Tjian","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, Li Ka Shing Center for Biomedical and Health Sciences, CIRM Center of Excellence, University of California, Howard Hughes Medical Institute, Berkeley, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8874-8704","authenticated-orcid":true,"given":"Nathaniel","family":"Heintz","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"4374","published-online":{"date-parts":[[2019,12,23]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"4187","DOI":"10.1093\/hmg\/ddr346","article-title":"MeCP2 rett mutations affect large scale chromatin organization","volume":"20","author":"Agarwal","year":"2011","journal-title":"Human Molecular Genetics"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/13810","article-title":"Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2","volume":"23","author":"Amir","year":"1999","journal-title":"Nature Genetics"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1097\/00005072-199503000-00006","article-title":"Selective dendritic alterations in the cortex of rett syndrome","volume":"54","author":"Armstrong","year":"1995","journal-title":"Journal of Neuropathology and Experimental Neurology"},{"key":"bib4","article-title":"Decoding 5hmC as an active chromatin mark in the brain and its link to Rett Syndrome","author":"Ayata","year":"2013","unstructured":"Ayata P. 2013. 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