# Discovering human divergent activity-regulated elements using comparative, computational, and functional approaches

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $832,100

## Abstract

PROJECT SUMMARY
New experiences elicit distinct patterns of brain activity, leading to the changes in gene expression, neuronal
properties, and connectivity that underlie brain plasticity. In humans, the period of enhanced plasticity during
brain development is particularly protracted compared to other species. However, the mechanisms and extent
to which human neurons have changed to support increased plasticity remain unknown. Furthermore, although
prolonged developmental plasticity may support increased cognitive capabilities and behavioral flexibility, it may
also increase vulnerability to neurodevelopmental disorders. Neuronal plasticity depends on activity-regulated
changes in gene expression that are controlled by activity-responsive genomic regulatory elements. Although
we and others have identified regulatory elements as prominent substrates of human-specific evolutionary
change, recent atlases of postmortem human and non-human primate brains overlook such dynamic stimulus-
responsive regulatory elements. Without training on context-dependent data, current computational models that
infer regulatory function based on sequence fail to predict activity-dependent regulatory elements. We
hypothesize that there have been genetic changes in human divergent activity-regulated elements (hDAREs)
and that we can discover these human-specific genetic underpinnings of plasticity using genome-wide
approaches. We will use experimental and computational methods to predict and compare the activity-regulated
responses of human neurons versus neurons from rhesus macaque and chimpanzee. We have developed
innovative model systems that will allow us to stimulate physiological activity states in previously inaccessible
primate neurons, machine learning models to predict regulatory function based on sequence, and massively
parallel reporter assays and CRISPRi assays that will allow us to assess the function of candidate hDAREs.
Through the successful completion of these studies, we will determine which genomic elements and genetic
changes underlie activity-dependent responses in human neurons and the extent to which changes in these
elements represent a major substrate of evolutionary selection in the human lineage. This will lay the groundwork
for further phenotypic characterization of cellular plasticity mechanisms in the developing human brain.
Additionally, these datasets will provide a valuable resource for dissecting genetic mechanisms of
neurodevelopmental disorders.

## Key facts

- **NIH application ID:** 10779701
- **Project number:** 1R01MH134981-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** KATHERINE S. POLLARD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $832,100
- **Award type:** 1
- **Project period:** 2023-09-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10779701

## Citation

> US National Institutes of Health, RePORTER application 10779701, Discovering human divergent activity-regulated elements using comparative, computational, and functional approaches (1R01MH134981-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10779701. Licensed CC0.

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