# Functional elucidation of the sequence-encoded regulatory activity of enhancers in vivo in the brain

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $416,244

## Abstract

SUMMARY
Once considered junk, non-coding regions of the genome have emerged as central components of evolution,
development, and disease. The most common non-coding regulatory elements in the human genome are
enhancers, which ensure expression of target genes at the right time in the right cells by controlling their
activation. Perturbation to enhancer function is widely accepted as a major, but still poorly understood,
component of human brain evolution and disease. There have been major and continuing advances in
annotating enhancers and predicting activity of these elements in cells and tissues, including the brain. Despite
these advances, predicting the sequence-encoded function of enhancers remains a major challenge. Further,
the dynamic and context-dependent chromosomal interactions, epigenetic modifications, and transcription
factor activity that ultimately determine enhancer-mediated gene regulation generally remain poorly
understood. This represents a significant barrier in understanding the function of enhancers and in interpreting
the effect of enhancer sequence variation on human brain development, evolution and disease. As such, there
is critical need to determine the relationship between sequence and function for regulatory DNA, and
to define the determinants of enhancer activity and gene regulation in the brain. In the initial early stage
investigator MIRA funding, we established a productive research program focused elucidating enhancer-
mediated gene regulatory wiring in the mammalian brain. We paired functional assays with genetic and
genomic approaches to model the function of enhancers, transcription factors, and chromatin remodeling
proteins in normal and pathogenic brain development. The overarching goals of our MIRA research program
are to: 1) Extend and apply methods to define sequence-encoded enhancer activity in the mammalian brain, 2)
Determine the molecular mechanisms of enhancer-mediated gene regulation and transcriptional programming
in the brain, and 3) Characterize the consequences of regulatory sequence variation to understand the role of
enhancer DNA in the development, evolution, and disorders of the mammalian brain. In the renewal period, we
will apply integrative genetic, genomic, and neuroscience methods to address key gaps in the understanding of
sequence-encoded enhancer function and to answer fundamental questions regarding gene regulation in the
brain. Our work will address basic and translationally-relevant questions regarding the sufficiency and
necessity of enhancers for neurodevelopmental gene regulation, and will advance the emerging field of
enhancer-based tools for labeling and manipulation of cell types in the brain. Overall, our contributions will help
to decipher how transcriptional control is encoded at the genetic and epigenetic level and to illuminate the gene
regulatory circuitry of the mammalian brain.

## Key facts

- **NIH application ID:** 10543480
- **Project number:** 5R35GM119831-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Alexander Nord
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $416,244
- **Award type:** 5
- **Project period:** 2016-09-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10543480

## Citation

> US National Institutes of Health, RePORTER application 10543480, Functional elucidation of the sequence-encoded regulatory activity of enhancers in vivo in the brain (5R35GM119831-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10543480. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*