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Here, using single-molecule localization microscopy, we show that disease-inducing Huntingtin (mHtt) protein fragments display three distinct dynamic states in living cells \u2013 1) fast diffusion, 2) dynamic clustering and 3) stable aggregation. Large, stable aggregates of mHtt exclude chromatin and form 'sticky' decoy traps that impede target search processes of key regulators involved in neurological disorders. Functional domain mapping based on super-resolution imaging reveals an unexpected role of aromatic amino acids in promoting protein-mHtt aggregate interactions. Genome-wide expression analysis and numerical simulation experiments suggest mHtt aggregates reduce transcription factor target site sampling frequency and impair critical gene expression programs in striatal neurons. Together, our results provide insights into how mHtt dynamically forms aggregates and disrupts the finely-balanced gene control mechanisms in neuronal cells.<\/jats:p>","DOI":"10.7554\/elife.17056","type":"journal-article","created":{"date-parts":[[2016,8,3]],"date-time":"2016-08-03T03:59:20Z","timestamp":1470196760000},"source":"Crossref","is-referenced-by-count":100,"title":["Real-time imaging of Huntingtin aggregates diverting target search and gene transcription"],"prefix":"10.7554","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2981-6615","authenticated-orcid":true,"given":"Li","family":"Li","sequence":"first","affiliation":[{"name":"Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States"},{"name":"LKS Bio-medical and Health Sciences Center, CIRM Center of Excellence, University of California, Berkeley, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Liu","sequence":"additional","affiliation":[{"name":"Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Dong","sequence":"additional","affiliation":[{"name":"Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Li","sequence":"additional","affiliation":[{"name":"Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesley R","family":"Legant","sequence":"additional","affiliation":[{"name":"Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan 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