# Deciphering the regulatory principles governing enhancer specificity

> **NIH NIH DP2** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $164,895

## Abstract

Abstract
Enhancers are the genomic elements that encode the instructions for when and where genes are
expressed during development. The majority of mutations leading to disease are thought to reside in
enhancers. However, we do not understand which changes in enhancer sequence are inert sequence
variations between individuals or populations and which impact gene regulation and cellular integrity.
These fundamental questions remain unsolved, because we cannot relate enhancer sequence to gene
expression and phenotype. This gap in our knowledge is stalling our ability to interpret genomic data
and understand development, cellular integrity, and diseases. Enhancer sequences provide a scaffold for
transcription factors to bind to, by recognizing specific signatures in the DNA. The physical constraints
that govern how these proteins interact with enhancer DNA could lead to a set of grammatical
constraints that can be used to understand the relationship between enhancer sequence and tissue
specific gene expression. I propose the development of a toolkit of methodologies and approaches to
decipher the grammatical constraints on tissue specific enhancer activity. I will use highly parallel
functional reporter assays, high-throughput genotype to phenotype studies along with biochemical
assays, synthetic biology, and loss of function strategies. These experiments will be carried out in the
chordate Ciona intestinalis, as it is a unique system in which millions of enhancer variants can be
assayed for function in all cells of a developing embryo. Work in Ciona will be complemented with
experiments in chick, mouse and tissue culture to directly inform vertebrate development and pinpoint
mutations causing disease. Determining the ‘genetic code’ that relates the coding sequences of genes
into protein has provided detailed insight into a major component of our genome. Once we have a
similar code to decipher the instructions for when and where these genes are expressed, we will have
powerful tools to understand how the genome encodes the instructions for building and maintaining
life.

## Key facts

- **NIH application ID:** 10319729
- **Project number:** 3DP2HG010013-01S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Emma Kirsten Farley
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $164,895
- **Award type:** 3
- **Project period:** 2021-02-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10319729

## Citation

> US National Institutes of Health, RePORTER application 10319729, Deciphering the regulatory principles governing enhancer specificity (3DP2HG010013-01S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10319729. Licensed CC0.

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