# Uncovering fundamentals of gene regulation by enhancers

> **NIH NIH R35** · STANFORD UNIVERSITY · 2024 · $472,618

## Abstract

PROJECT SUMMARY/ABSTRACT
A class of cis-regulatory elements, called enhancers, plays a central role in orchestrating spatiotemporally
precise gene expression programs during development. Perturbations in enhancer sequence or regulation can
lead to disease, including congenital malformations and cancer. Furthermore, enhancer sequence divergence is
emerging as an important mediator of human phenotypic variation. Key features of enhancers include their role
as major sites for transcription factor (TF) and coactivator binding in the genome, as well as their ability to activate
transcription over long genomic distances from their target promoters. Indeed, at some genomic loci enhancers
can regulate promotes at distances of over a megabase away. Such long-range function raises a question of
how is regulatory specificity within chromosomal domains containing many cis-regulatory elements
accomplished to allow for precise and robust gene regulation during development and in tissue homeostasis?
Proposed research program focuses on addressing fundamental knowledge gaps in enhancer biology and long-
range gene regulation. We will utilize novel genomic and computational approaches to systematically probe how
enhancer-promoter genomic distance, 3D contacts and inherent features of cis-regulatory elements influence
transcriptional outputs, and how a broader genomic and epigenomic environment modulates promoter
responsiveness to enhancers. We will complement these studies with live-cell and multiplexed DNA FISH
imaging of model loci where enhancers regulate their target genes over ultra-long genomic distances. We will
track movement of cis-regulatory elements and visualize nascent transcripts to capture the kinetic behavior of
enhancers and promoters and its relationship with the discontinuous nature of transcription. We will introduce
genetic perturbations to address how a new class of structural elements identified in our previous studies
mediates robust transcriptional regulation. Finally, through precise modulation of TF and coactivator dosage at
physiological levels, we will explore features that confer sensitivity or robustness of enhancers and gene
expression to changes in trans-activator concentrations. Altogether, the proposed research will yield new
concepts and quantitative models of long-range gene control, with broad future implications for understanding
and treatment of human disease.

## Key facts

- **NIH application ID:** 10841960
- **Project number:** 2R35GM131757-06
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Joanna Wysocka
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $472,618
- **Award type:** 2
- **Project period:** 2019-05-15 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841960

## Citation

> US National Institutes of Health, RePORTER application 10841960, Uncovering fundamentals of gene regulation by enhancers (2R35GM131757-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10841960. Licensed CC0.

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