Ruiz Buendía Gustavo A, Leleu Marion, Marzetta Flavia, Vanzan Ludovica, Tan Jennifer Y, Ythier Victor, Randall Emma L, Marques Ana C, Baubec Tuncay, Murr Rabih, Xenarios Ioannis, Dion Vincent
Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland.
School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
Sci Adv. 2020 Jul 3;6(27):eaaz4012. doi: 10.1126/sciadv.aaz4012. eCollection 2020 Jul.
Expanded CAG/CTG repeats underlie 13 neurological disorders, including myotonic dystrophy type 1 (DM1) and Huntington's disease (HD). Upon expansion, disease loci acquire heterochromatic characteristics, which may provoke changes to chromatin conformation and thereby affect both gene expression and repeat instability. Here, we tested this hypothesis by performing 4C sequencing at the and loci from DM1 and HD-derived cells. We find that allele sizes ranging from 15 to 1700 repeats displayed similar chromatin interaction profiles. This was true for 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 the conformation of the surrounding chromatin. We conclude that CAG/CTG repeat expansions are not enough to alter chromatin conformation in cis. Therefore, it is unlikely that changes in chromatin interactions drive repeat instability or changes in gene expression in these disorders.
扩展的CAG/CTG重复序列是13种神经疾病的基础，包括1型强直性肌营养不良（DM1）和亨廷顿舞蹈症（HD）。重复序列扩展后，疾病位点获得异染色质特征，这可能引发染色质构象变化，从而影响基因表达和重复序列的不稳定性。在此，我们通过对DM1和HD来源细胞的相关位点进行4C测序来验证这一假设。我们发现，长度在15至1700个重复序列之间的等位基因显示出相似的染色质相互作用图谱。两个位点以及具有不同DNA甲基化水平和CTCF结合情况的等位基因均是如此。此外，扩展的CAG重复序列片段的异位插入并未改变周围染色质的构象。我们得出结论，CAG/CTG重复序列扩展不足以顺式改变染色质构象。因此，在这些疾病中，染色质相互作用的变化不太可能驱动重复序列的不稳定性或基因表达的改变。
