# Mechanisms of coordinate gene regulation by transcription factors

> **NIH NIH R35** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2024 · $448,875

## Abstract

ABSTRACT
Many of the molecular mechanisms underlying well-characterized robust and rapidly inducible transcriptional
responses are shared among other systems, so we use hormone-induced transcriptional responses to study
gene regulation. We use rapid kinetic regulation and perturbation of transcription cascades, transcription
factors, and cofactors to identify key mechanisms, genes, and regulatory elements that are critical for hormone
signaling. Transcription factors act as activators or repressors and interface with a constellation of accessory
cofactors to regulate distinct steps in the transcription to coordinate gene expression, but the molecular
functions of the vast majority of transcription factors remain uncharacterized. We use molecular genomics
assays and computational methods to classify transcription factors by their molecular function, as opposed to
broad activator and repressor classes, in order to understand the context specificity of gene regulation. We
found that the estrogen receptor transcription factor may compete with other transcription factors for limiting
cofactors to mediate estrogen-induced repression. We will develop genetic tools to uncouple activation and
repression to test various models of repression, such as squelching cofactors from repressed genes. The
genes and regulatory elements that are downstream of the first wave of transcriptional response are critical for
propagating regulatory cascades. We generate high resolution, genome-wide time course data of regulatory
element activity and nascent transcription upon stimulation of differentiation processes. We construct
mechanistically interpretable networks to identify effector genes and regulatory elements that are critical for
signaling in regulatory cascades. Our research reveals basic principles and rules that govern transcription
factor specificity in order to understand how genetics, nutrition, and environmental factors contribute to
variation in transcriptional programs that can lead to disease states or ineffective therapies.

## Key facts

- **NIH application ID:** 10763594
- **Project number:** 2R35GM128635-06
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Michael Joseph Guertin
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $448,875
- **Award type:** 2
- **Project period:** 2018-08-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10763594

## Citation

> US National Institutes of Health, RePORTER application 10763594, Mechanisms of coordinate gene regulation by transcription factors (2R35GM128635-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10763594. Licensed CC0.

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