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 journalArticle

20 Citations (Scopus)

Abstract

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
JournalCell
Volume175
Issue number1
DOIs
StatePublished - Sep 20 2018

Fingerprint

Microsatellite Repeats
Chromatin
Fragile X Syndrome
CpG Islands
Genes
Nucleic Acid Repetitive Sequences
DNA sequences
Human Genome
Epigenomics
Genome

Keywords

  • 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)

Cite this

Sun, J. H., Zhou, L., Emerson, D. J., Phyo, S. A., Titus, K. R., Gong, W., ... Phillips-Cremins, J. E. (2018). Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries. Cell, 175(1), 224-238.e15. https://doi.org/10.1016/j.cell.2018.08.005

Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries. / Sun, James H.; Zhou, Linda; Emerson, Daniel J.; Phyo, Sai A.; Titus, Katelyn R.; Gong, Wanfeng; Gilgenast, Thomas G.; Beagan, Jonathan A.; Davidson, Beverly L.; Tassone, Flora; Phillips-Cremins, Jennifer E.

In: Cell, Vol. 175, No. 1, 20.09.2018, p. 224-238.e15.

Research output: Contribution to journalArticle

Sun, JH, Zhou, L, Emerson, DJ, Phyo, SA, Titus, KR, Gong, W, Gilgenast, TG, Beagan, JA, Davidson, BL, Tassone, F & Phillips-Cremins, JE 2018, 'Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries', Cell, vol. 175, no. 1, pp. 224-238.e15. https://doi.org/10.1016/j.cell.2018.08.005
Sun JH, Zhou L, Emerson DJ, Phyo SA, Titus KR, Gong W et al. Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries. Cell. 2018 Sep 20;175(1):224-238.e15. https://doi.org/10.1016/j.cell.2018.08.005
Sun, James H. ; Zhou, Linda ; Emerson, Daniel J. ; Phyo, Sai A. ; Titus, Katelyn R. ; Gong, Wanfeng ; Gilgenast, Thomas G. ; Beagan, Jonathan A. ; Davidson, Beverly L. ; Tassone, Flora ; Phillips-Cremins, Jennifer E. / Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries. In: Cell. 2018 ; Vol. 175, No. 1. pp. 224-238.e15.
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