# Trinucleotide repeat disorders and the 3D genome

> **NIH NIH F30** · UNIVERSITY OF PENNSYLVANIA · 2021 · $25,721

## Abstract

Project Summary
 Unstable expansion of repetitive DNA sequences termed short tandem repeats (STRs) serves as the
mechanistic basis for more than 25 inherited human disorders. Patients with unstable repeat expansion
diseases suffer from a complex array of symptoms, including: cardiac defects, cataracts, anxiety, hyperactivity,
low IQ, social deficits, respiratory defects and seizures. In some diseases, such as Fragile X Syndrome and
Freidreich’s Ataxia, the downstream phenotype is mediated in large part by reduced gene expression. In all of
these diseases, continuous repeat expansion is associated with disease severity. Treating trinucleotide repeat
disorders is thus complex because the primary effectors of disease include both the continuous expansion of
repetitive sequences as well as disrupted expression of the gene containing the repeat. Thus, an increased
understanding of the molecular mechanisms governing STR instability and expansion related gene
dysregulation would facilitate efforts to develop therapies to prevent and treat repeat expansion disorders.
 In our preliminary work, we introduce the higher order chromatin architecture as a new dimension in
understanding these features in repeat expansion disorders. Our data shows that (1) the large majority of disease
associated STRs are located precisely at boundaries demarcating 3D genome folding domains termed
topologically associating domains (TADs) and subTADs and (2) repeat expansion in the FMR1 gene, the genetic
driver for Fragile X Syndrome, results in CTCF occupancy ablation and large-scale TAD/subTAD reorganization
in a manner that correlates with STR tract length, disease severity, and transcriptional disruption of FMR1.
Given the increasing importance of the 3D genome, there is a critical need to extend our preliminary data to
understand how the 3D genome may be perturbed by trinucleotide repeat expansion and whether this
perturbation could contribute to the primary effectors of disease originating from the causal gene itself: repeat
instability and dysregulated gene expression. This proposal outlines the next steps doing so. In the first aim, I
will perform genome engineering experiments to determine if the domain reorganization we have observed
around FMR1 contributes to decreased gene expression. In the second aim, I will create high resolution
topological maps around the FXN gene, the genetic driver for Freidreich’s ataxia, the determine whether
boundary disruption is present in an additional trinucleotide repeat disorder. In the third aim, I will perform
additional genome editing experiments to elucidate whether domain boundary disruptions can influence repeat
instability and gene expression of the FXN gene. In sum, the accomplishment of these aims would demonstrate
that the 3D genome can be perturbed in repeat expansion disorders and that this perturbation can mediate
repeat instability and disrupted gene expression. Ultimately, we could use these results to determine whether
...

## Key facts

- **NIH application ID:** 10251290
- **Project number:** 5F30HD098015-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Linda Zhou
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $25,721
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-05-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10251290

## Citation

> US National Institutes of Health, RePORTER application 10251290, Trinucleotide repeat disorders and the 3D genome (5F30HD098015-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10251290. Licensed CC0.

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