PT  - JOURNAL ARTICLE
AU  - James Sun
AU  - Linda Zhou
AU  - Daniel J. Emerson
AU  - Thomas G. Gilgenast
AU  - Katelyn Titus
AU  - Jonathan A. Beagan
AU  - Jennifer E. Phillips-Cremins
TI  - Genetic drivers of repeat expansion disorders localize to 3-D chromatin domain boundaries
AID  - 10.1101/191213
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 191213
4099  - http://biorxiv.org/content/early/2017/09/20/191213.short
4100  - http://biorxiv.org/content/early/2017/09/20/191213.full
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.