# Combinatorial Biology of Gene Regulation for Cellular Engineering

> **NIH NIH DP2** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $403,645

## Abstract

Project summary
There is a fundamental gap in our ability to target the non-coding genome for therapeutic benefit. While the
druggable genome is expanding, it still remains confined to the tiny fraction of the human genome encoding for
genes. This exclusion of the non-coding genome is unfortunate, as these regions can provide a powerful han-
dle to finely control cellular responses and are more flexible than gene-targeting approaches. Our long-term
goal is to develop a predictive and functional understanding of the non-coding genome, which will elucidate
how these regions can be specifically targeted for genomic medicine. Towards this long-term goal, the objec-
tive of this proposal is to systematically interrogate the combinatorial biology of enhancer gene regulation. We
will pursue this objective at three levels: from the action of multiple protein effectors on individual enhancers, to
the cooperativity between multiple enhancers, and culminating in the genome-wide coordination of multiple
transcription factors to influence cell state. We have developed an innovative platform that enables high
throughput assessment of combinatorial gene regulation, which will play a central role in this proposal. Our
overall hypothesis is that, across multiple levels, combinatorial gene regulation uses a small set of components
to create a broad spectrum of functionalities. We further hypothesize that the rules governing these functionali-
ties can be explained by defining the key components, and examining how each functions alone and in simple
combinations. The rationale for the proposed research is that a fundamental understanding of combinatorial
gene regulation will enable predictive targeting of the non-coding genome for genomic medicine, leading to in-
novative approaches to the prevention and treatment of disease. This proposal opens new research horizons
to understanding the underlying concepts of combinatorial gene regulation and the epigenetic mechanisms un-
derlying enhancer function, and for improved methods to modulate enhancer activity and engineer custom
gene regulatory programs. Ultimately, this knowledge will be required to harness the genome for engineering
and to understand how non-coding regulators contribute to development and disease.

## Key facts

- **NIH application ID:** 10372278
- **Project number:** 3DP2GM128203-01S2
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Gary Chung Hon
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $403,645
- **Award type:** 3
- **Project period:** 2017-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372278

## Citation

> US National Institutes of Health, RePORTER application 10372278, Combinatorial Biology of Gene Regulation for Cellular Engineering (3DP2GM128203-01S2). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10372278. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*