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Three-dimensional chromatin interactions remain stable upon CAG/CTG repeat expansion

Ruiz Buendía, Gustavo A., Leleu, Marion, Marzetta, Flavia, Vanzan, Ludovica, Tan, Jennifer, Ythier, Victor, Randall, Emma L., Marques, Ana C., Baubec, Tuncay, Murr, Rabih, Xenarios, Ioannis and Dion, Vincent 2020. Three-dimensional chromatin interactions remain stable upon CAG/CTG repeat expansion. Science Advances 6 (27) , eaaz4012. 10.1126/sciadv.aaz4012

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Abstract

Expanded CAG/CTG repeats underlie thirteen neurological disorders, including myotonic dystrophy (DM1) and Huntington’s disease (HD). Upon expansion, disease loci acquireb characteristics, which may provoke changes to chromatin conformation. These changes could thereby affect both gene expression and repeat instability. Here we tested this hypothesis directly by performing 4C sequencing at the DMPK and HTT loci from DM1 and HD patient-derived cells. We find that allele sizes ranging from 15 to 1,700 repeats displayed strikingly similar chromatin interaction profiles. This was true at both loci and for alleles with different DNA methylation levels and CTCF binding. Moreover, the ectopic insertion of an expanded CAG repeat tract did not change chromatin conformation of the surrounding region. We conclude that extensive changes in heterochromatic properties are not enough to alter chromatin conformation at expanded CAG/CTG repeat loci and that such changes are unlikely to drive repeat expansions or changes in gene expression.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Association for the Advancement of Science
ISSN: 2375-2548
Date of First Compliant Deposit: 24 August 2020
Date of Acceptance: 4 May 2020
Last Modified: 24 Aug 2020 13:50
URI: http://orca.cf.ac.uk/id/eprint/131504

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