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bioRxiv · 10.1101/191213

Genetic drivers of repeat expansion disorders localize to 3-D chromatin domain boundaries

Sun, J.·Zhou, L.·Emerson, D. J.·Gilgenast, T. G.·Titus, K.·Beagan, J. A.·Phillips-Cremins, J. E.
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Abstract

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.

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Sun, J., Zhou, L., Emerson, D. J., Gilgenast, T. G., Titus, K., Beagan, J. A., Phillips-Cremins, J. E.. 2017-09-20. Genetic drivers of repeat expansion disorders localize to 3-D chromatin domain boundaries. https://doi.org/10.1101/191213

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