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Cell. 2018 Sep 20;175(1):224-238.e15. doi: 10.1016/j.cell.2018.08.005. Epub 2018 Aug 30.

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

Author information

1
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Genomics and Computational Biology Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
4
The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, CA 95616, USA; MIND Institute, UC Davis, Sacramento, CA 95616, USA.
6
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jcremins@seas.upenn.edu.

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.

KEYWORDS:

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

PMID:
30173918
PMCID:
PMC6175607
[Available on 2019-09-20]
DOI:
10.1016/j.cell.2018.08.005

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