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

James Sun, Linda Zhou, Daniel J. Emerson, Thomas G. Gilgenast, Katelyn Titus, Jonathan A. Beagan, View ORCID ProfileJennifer E. Phillips-Cremins
doi: https://doi.org/10.1101/191213
James Sun
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104
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Linda Zhou
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104
2Genomics and Computational Biology Program, Perelman School of Medicine, University of Pennsylvania
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Daniel J. Emerson
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104
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Thomas G. Gilgenast
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104
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Katelyn Titus
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104
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Jonathan A. Beagan
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104
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Jennifer E. Phillips-Cremins
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104
2Genomics and Computational Biology Program, Perelman School of Medicine, University of Pennsylvania
3Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania
4Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104
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  • ORCID record for Jennifer E. Phillips-Cremins
  • For correspondence: jcremins@seas.upenn.edu
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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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Posted September 20, 2017.
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Genetic drivers of repeat expansion disorders localize to 3-D chromatin domain boundaries
James Sun, Linda Zhou, Daniel J. Emerson, Thomas G. Gilgenast, Katelyn Titus, Jonathan A. Beagan, Jennifer E. Phillips-Cremins
bioRxiv 191213; doi: https://doi.org/10.1101/191213
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Genetic drivers of repeat expansion disorders localize to 3-D chromatin domain boundaries
James Sun, Linda Zhou, Daniel J. Emerson, Thomas G. Gilgenast, Katelyn Titus, Jonathan A. Beagan, Jennifer E. Phillips-Cremins
bioRxiv 191213; doi: https://doi.org/10.1101/191213

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