# Multiscale genomic decryption of regulatory DNA

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $387,585

## Abstract

Project Summary/Abstract:
Regulatory DNA encodes signals that are recognized by transcriptional regulators to drive development- and
stimulus-specific patterns of gene expression. While individual DNA binding sites recognized by transcription
factors are often short and promiscuous in the genome, functional regulatory elements usually contain several
closely spaced binding sites that specify the cooperative assembly of regulatory factors on DNA. Multiple lines
of evidence suggest the configuration of these binding sites, including their relative binding affinity, spacing and
orientation, play important roles in the context-dependent recruitment of RNA polymerase II to drive transcription.
Furthermore, regulatory elements do not function independently in the genome. Proper gene regulation often
depends on multiple regulatory elements scattered across gene loci that work in concert to enhance or silence
target promoters. Yet despite extensive research efforts, our understanding of how regulatory DNA is organized
is still rudimentary, limiting our ability to accurately model transcriptional networks and interpret the function of
genetic variants. My laboratory seeks answers to these fundamental biological questions using a combination of
experimental and computational approaches to decode regulatory DNA. Previous efforts to investigate the
function of regulatory regions have typically relied on indirect measurements of transcriptional activity, such as
the profiling of epigenetic markers, transcription factor binding, chromatin accessibility, or the expression of
nearby genes or reporters. We have found that precise measurements of transcription initiation, which record
the frequency and base positions where RNAPII initiates transcription, yield novel insights into the roles of
transcription factor motifs and other regulatory DNA features in regulating transcription. Transcription initiation
profiling also provides sensitive and precise measurements of activation at promoter-distal regulatory elements,
enabling us to track the functional interactions between promoter and enhancer elements in the genome in the
context of chromatin modifications and changes in 3D genome structure. Using these approaches we will explore
how transcription factors exert activating or inhibitory effects on individual transcription start sites (TSS),
depending on their spatial location within regulatory elements, and investigate how multiple regulatory elements
work together to drive the transcription of target genes. These studies will greatly expand the ruleset to interpret
how regulatory DNA and genetic variation affect gene regulation.

## Key facts

- **NIH application ID:** 10624086
- **Project number:** 1R35GM149520-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Christopher W Benner
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $387,585
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10624086

## Citation

> US National Institutes of Health, RePORTER application 10624086, Multiscale genomic decryption of regulatory DNA (1R35GM149520-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10624086. Licensed CC0.

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