# Illuminating transcriptional condensates using an integrated approach

> **NIH NIH DP2** · UNIVERSITY OF PENNSYLVANIA · 2021 · $1,462,500

## Abstract

Project Summary
Gene regulation is fundamental for every aspect of human function and errors in this process are
key drivers for many diseases, including cancer. Proper gene expression requires a large number
of proteins to assemble and function in a highly coordinated manner, but how this is achieved is
still not understood. Recent studies revealed that some transcriptional regulators form dynamic
high local concentration assemblies termed transcriptional condensates or hubs. These
condensates are driven by weak multivalent interactions, which have biophysical properties and
regulatory mechanisms distinct from the long-studied ‘lock and key’-type of high-affinity
interactions. As such, the discovery of transcriptional condensates offers a new molecular
principle to explain how transcription is organized. However, it remains unclear how exactly
transcriptional condensates from, how they are regulated and dysregulated, and how they impact
gene control during development and in diseases. This is largely due to the lack of experimental
strategies to precisely control condensate formation and its properties for functional and
mechanistic interrogations. This project uniquely addresses these major gaps by leveraging
naturally occurring disease mutations. We discovered a series of oncogenic mutations in a
chromatin regulator that promote aberrant formation of transcriptional condensates. These
‘acquired’ condensates strongly correlated with oncogenic gene activation and tumorigenesis,
providing one of the first examples linking aberrant condensate formation to human disease.
Using these mutations as the stepping-stone, this project aims to develop a more in-depth and
broad understanding of transcriptional condensates and establish their dysregulation as a new
pathognenic mechanism. Specifically, we will ask three major questions: (1) How do
transcriptional condensates form at the molecule level? (2) What are the regulatory functions
enabled by transcriptional condensates? (3) Can transcriptional condensates be therapeutically
targeted? We will integrate cutting-edge approaches in structural biology, single-molecule
imaging, gene regulation, epigenetics, cancer biology, and high-throughput drug discovery to
address these questions. Successful completion of this project would offer definitive evidence and
mechanistic insights needed to establish a new model of gene control. It also has the potential to
transform how we think about and target gene dysregulation in diseases. The ideal experimental
system we discovered and extensive expertise of my lab put us in a unique position to embark on
this highly ambitious but urgently needed research program.

## Key facts

- **NIH application ID:** 10245754
- **Project number:** 1DP2HG012443-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Liling Wan
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,462,500
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10245754

## Citation

> US National Institutes of Health, RePORTER application 10245754, Illuminating transcriptional condensates using an integrated approach (1DP2HG012443-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10245754. Licensed CC0.

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