# Mapping enhancer-gene regulation in single cells to connect genetic variants to target genes and cell types

> **NIH NIH R35** · STANFORD UNIVERSITY · 2023 · $473,100

## Abstract

Project Summary
The human genome encodes over 2 million DNA regulatory elements called enhancers that
control gene expression in specific cell types and states. Enhancers harbor tens of thousands of
genetic variants that influence risk for common diseases and traits. Each of these enhancer
variants could reveal insights into the molecular mechanisms of human diseases. Yet, we have
lacked tools to systematically map which enhancers regulate which genes in each of the
thousands of cell types in the human body.
To address this challenge, we have recently developed CRISPR tools to experimentally test
thousands of enhancers in parallel, and discovered a simple computational model that can predict
enhancer-gene regulation from chromatin state. These nascent technologies suggest a new
strategy to map enhancers across many cell types to connect noncoding variants to target genes.
Here we will develop and extend these new technologies to map and predict enhancer-gene
connections at single-cell resolution. First, we will characterize how enhancer function changes
across developmental trajectories, by combining our CRISPR tool with a new single-cell readout
method to survey thousands of enhancer-gene connections in differentiating vascular cells.
Second, we will develop a computational model that can predict enhancer-gene regulation from
single-cell measurements of chromatin accessibility. Third, we will apply these tools to build maps
of enhancer-gene regulation in the adult human heart, and demonstrate the utility of these maps
by characterizing genetic variants associated with coronary artery disease.
These technologies will enable mapping enhancer-gene regulation in many cell types, building a
foundational resource for connecting noncoding genetic variants to their molecular functions. This
approach will be broadly applicable to any common, complex disease. This proposal builds on
the PI’s experiences in genomics and team science with the ENCODE Consortium and Variant-
to-Function Initiative. This R35 Genomic Innovator Award will help the PI launch a career at the
interface of human genomics and cardiovascular disease that will include significant contributions
to team science efforts. The environment at Stanford University in the Department of Genetics
and Children’s Heart Center is ideal for supporting these scientific and leadership roles.

## Key facts

- **NIH application ID:** 10657459
- **Project number:** 5R35HG011324-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** JESSE M ENGREITZ
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $473,100
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10657459

## Citation

> US National Institutes of Health, RePORTER application 10657459, Mapping enhancer-gene regulation in single cells to connect genetic variants to target genes and cell types (5R35HG011324-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10657459. Licensed CC0.

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