# Deciphering the mechanism of long-range gene regulation in vivo

> **NIH NIH DP2** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $1,413,000

## Abstract

PROJECT SUMMARY
Distant-acting (“remote”) transcriptional enhancers bound by transcription factors (TFs) drive gene expression
patterns in space and time. The importance of this function is underscored by mounting evidence linking
mutations affecting remote enhancers to human disease. What remains unclear is how these remote enhancers
regulate their target genes over long genomic distances, often skipping intervening genes. Remote enhancers
typically interact with target promoters with the support of higher-order chromatin organization, but disruption of
this chromatin organization does not abolish enhancer–promoter interactions. What additional factors regulate
these long-range regulatory interactions remains largely unexplored. To address this central question, the
proposed project will use a novel gain-of-function approach to identify cis-regulatory sequences that mediate
long-range enhancer–promoter communication in the context of mammalian development. Traditional methods
that assess in vivo enhancer activity rely on enhancer-reporter transgenesis; however, technical limitations
preclude this approach from assessing long-range enhancer activity. The proposed work overcomes this
limitation by utilizing efficient enhancer replacement technology in mice to systematically characterize in vivo
long-range enhancer activity and identify cis-regulatory sequences that are critical for this long-range activity. To
determine the mechanism of long-range regulation by these remote control elements and identify regulatory
proteins that bind them, this work will use a multidisciplinary approach to map and visualize enhancer–promoter
contacts at macromolecular resolution. Functional characterization of remote control elements will expand the
repertoire of known cis-regulatory elements, provide a novel general mechanism for long-range enhancer–
promoter communication, and substantially advance knowledge of the role of 3D-genome organization in the
context of development and disease.

## Key facts

- **NIH application ID:** 10473041
- **Project number:** 1DP2GM149555-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Evgeny Kvon
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,413,000
- **Award type:** 1
- **Project period:** 2022-09-09 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10473041

## Citation

> US National Institutes of Health, RePORTER application 10473041, Deciphering the mechanism of long-range gene regulation in vivo (1DP2GM149555-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10473041. Licensed CC0.

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