Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries

James H. Sun, Linda Zhou, Daniel J. Emerson, Sai A. Phyo, Katelyn R. Titus, Wanfeng Gong, Thomas G. Gilgenast, Jonathan A. Beagan, Beverly L. Davidson, Flora Tassone, Jennifer E. Phillips-Cremins

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


More than 25 inherited human disorders are caused by the unstable expansion of repetitive DNA sequences termed short tandem repeats (STRs). A fundamental unresolved question is why some STRs are susceptible to pathologic expansion, whereas thousands of repeat tracts across the human genome are relatively stable. Here, we discover that nearly all disease-associated STRs (daSTRs) are located at boundaries demarcating 3D chromatin domains. We identify a subset of boundaries with markedly higher CpG island density compared to the rest of the genome. daSTRs specifically localize to ultra-high-density CpG island boundaries, suggesting they might be hotspots for epigenetic misregulation or topological disruption linked to STR expansion. Fragile X syndrome patients exhibit severe boundary disruption in a manner that correlates with local loss of CTCF occupancy and the degree of FMR1 silencing. Our data uncover higher-order chromatin architecture as a new dimension in understanding repeat expansion disorders. Short tandem repeats associated with human diseases such as fragile X syndrome localize to topological boundaries and can disrupt 3D chromatin structure.

Original languageEnglish (US)
Pages (from-to)224-238.e15
Issue number1
StatePublished - Sep 20 2018


  • 3D genome folding
  • fragile X syndrome
  • genome instability
  • higher-order chromatin architecture
  • short tandem repeats
  • subTADs
  • TADs
  • topologically associating domains
  • trinucleotide repeat expansion disorders

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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