# Targeted Gene Regulation Using Engineered Synthetic Transcriptional Regulators

> **NIH NIH F32** · UNIVERSITY OF CHICAGO · 2022 · $67,174

## Abstract

PROJECT ABSTRACT
Transcription factors are key functional proteins that regulate gene expression through direct interaction with
specific sequences of genomic DNA, thereby activating or repressing transcription. This highly conserved
process controls many central biological functions including cellular homeostasis, differentiation, and apoptosis.
Given this central role in regulating cell state and function, it is unsurprising that aberrant activity is implicated in
many diseases including neurological disorders, autoimmunity, diabetes, and cancer. In particular, the master
regulator MYC transcription factor is dysregulated in over half of all cancers, yet effective therapies targeting
MYC-driven gene programs have yet to be developed. While approaches involving direct targeting of MYC with
small molecules and antibodies or indirect targeting such as gene silencing have been explored, these are
associated with major drawbacks including weak binding interactions or activity, poor pharmacological
properties, and off-target effects. As an alternative approach, the Moellering lab recently developed a new class
of hyperstable synthetic DNA-binding domains derived from the transcription factor MAX that orthogonally self-
dimerize to sequence-specifically bind DNA with high affinity and specificity. These synthetic transcriptional
regulators (STRs) competitively inhibit the DNA binding of native dimers of MYC/MAX or MAX/MAX and contest
MYC-dependent gene expression. Building on this precedence, I hypothesize that the potency of these
compounds would be increased by covalently ligating split monomeric STRs to produce pre-organized dimeric
STRs. Additionally, I hypothesize that generating multi-functional STRs that recruit transcriptional machinery to
directed genomic sites would provide further control to inhibit MYC-dependent phenotypes. The proposed
research aims to explore these two potential routes for advancing the STR technology and evaluate their effects
on MYC-dependent gene expression and phenotypes. Together, this tandem approach will establish a new class
of potent MYC antagonists and provide mechanistic tools to study oncogenic gene expression in cells.
Additionally, this modular design strategy to develop transcription factor mimetics will provide a framework to
enable preparation of future constructs tailored towards other important transcription factors and genomic
targets.

## Key facts

- **NIH application ID:** 10538129
- **Project number:** 1F32GM148062-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Colin Stuart Swenson
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,174
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10538129

## Citation

> US National Institutes of Health, RePORTER application 10538129, Targeted Gene Regulation Using Engineered Synthetic Transcriptional Regulators (1F32GM148062-01). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/10538129. Licensed CC0.

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