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

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