RT Journal Article
SR Electronic
T1 Genetic drivers of repeat expansion disorders localize to 3-D chromatin domain boundaries
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 191213
DO 10.1101/191213
A1 James Sun
A1 Linda Zhou
A1 Daniel J. Emerson
A1 Thomas G. Gilgenast
A1 Katelyn Titus
A1 Jonathan A. Beagan
A1 Jennifer E. Phillips-Cremins
YR 2017
UL http://biorxiv.org/content/early/2017/09/20/191213.abstract
AB More than 25 inherited neurological disorders are caused by the unstable expansion of repetitive DNA sequences termed short tandem repeats (STRs). A fundamental unresolved question is why specific STRs are susceptible to unstable expansion leading to severe pathology, whereas tens of thousands of normal-length repeat tracts across the human genome are relatively stable. Here, we unexpectedly discover that nearly all STRs associated with repeat expansion diseases are located at boundaries demarcating 3-D chromatin domains. We find that boundaries exhibit markedly higher CpG island density compared to loci internal to domains. Importantly, disease-associated STRs are specifically localized to ultra-dense CpG island-rich boundaries, suggesting that these loci might be hotspots for epigenetic instability and topological disruption upon unstable expansion. In Fragile X Syndrome, mutation-length expansion at the Fmr1 gene results in severe disruption of the boundary between TADs. Our data uncover higher-order chromatin architecture as a new dimension in understanding the mechanistic basis of repeat expansion disorders.