# Evaluating novel architectural proteins as therapeutic targets for cohesin dysfunction

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2022 · $243,750

## Abstract

Abstract
 Cornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs
including the central nervous system, inducing a variable neurodevelopmental delay. CdLS is primarily caused
by mutations in regulatory or structural components of the cohesin complex, which are essential Structural
Maintenance of Chromosomes (SMC) protein-containing complexes that interact with chromatin and modulate
genome folding. It is hypothesized that CdLS symptoms are a consequence of transcriptional dysregulation
due to changes in genome architecture upon cohesin disruption. To date, there are no therapies aimed at
correcting cohesin dysfunction or chromatin misfolding directly. These issues are due, in part, to the paucity of
factors known to regulate cohesin-mediated chromatin folding. We performed a high-throughput fluorescent in
situ hybridization (Hi-FISH)-based screen in human cells, which uses Oligopaint probe technology to detect
and measure chromatin interactions in a large number of samples. We targeted ~8,000 human genes, which
represent the “druggable genome” and isolated five candidate genes whose depletion can offset cellular
phenotypes associated with cohesin dysfunction. The goal of this proposal is to characterize the role of these
novel ‘anti-cohesin factors’ in nuclear architecture and cohesin function and test the ability of their inhibition to
correct gene misexpression in CdLS models. Through understanding the molecular factors involved in cohesin
biology and chromatin folding, we can begin to consider targeted approaches to CdLS therapeutic
development.

## Key facts

- **NIH application ID:** 10593249
- **Project number:** 1R21HD107261-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Eric F. Joyce
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $243,750
- **Award type:** 1
- **Project period:** 2022-09-23 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10593249

## Citation

> US National Institutes of Health, RePORTER application 10593249, Evaluating novel architectural proteins as therapeutic targets for cohesin dysfunction (1R21HD107261-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10593249. Licensed CC0.

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