# Mechanisms of Genome Architecture Regulation in Motor Learning

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $415,538

## Abstract

The goals of the proposed research are to elucidate mechanisms of genome organization during neuronal
activity in vivo and determine the roles of these mechanisms in learning and memory. We recently discovered
that the sensory experience of animals controls the remodeling of neuronal genome architecture in the brain.
The rapid induction of local genomic interactions between gene regulatory enhancers and promoters drives the
upregulation of activity-dependent gene expression to promote motor learning. However, hundreds of genes are
downregulated with neuronal activity in vivo, a finding that has been observed in multiple brain areas with
unknown mechanisms and functions. This raises fundamental questions of what are the mechanisms that control
activity-dependent transcriptional repression and what are the functions of these large genetic programs in motor
learning. In this grant proposal, we will interrogate potential molecular mechanisms and biological functions of
3D genome organization at multiple scales in the control of gene repression.
 First, we will determine if neuronal activity might trigger sequence-specific transcription factors to remodel
local genome architecture including between gene regulatory enhancers and promoters. Based on our findings,
we will test the hypothesis that regulation of brain-enriched transcription factors triggers the breaking of
enhancer-promoter interactions in the presence of neuronal activity to repress gene transcription. Furthermore,
we will also test the hypothesis that local genome architecture maintained by these transcription factors play a
critical role for motor learning in mice. These experiments will shed light on molecular mechanisms that
dynamically regulate local genome architecture in the brain.
 Second, we will determine if remodeling of long-range genomic interactions including interactions
between different chromosomes might regulate activity-dependent gene repression. Based on our preliminary
findings, we will test the hypotheses that 1) in unstimulated neurons, genes form inter-chromosomal interactions
with specific nuclear bodies involved in active transcription and 2) weakening of gene interactions with these
nuclear bodies during neuronal activity attenuates gene expression. In addition, we will also test the hypothesis
that these nuclear bodies found in adult neurons play specific roles in the acquisition or expression of motor
memories in mice. These experiments will illuminate the roles of brain-enriched nuclear bodies in transcription
and long-term memory.
 The proposed research will potentially advance our understanding of genome organization principles at
both local and long-range genomic scales in the control of neural circuit refinement and adaptive changes in
organismal behavior. Because mutations of genome architectural proteins and synaptic proteins are linked to
disorders of cognition in humans, our research will also provide an integrated view on how sensory experiences
orch...

## Key facts

- **NIH application ID:** 10442579
- **Project number:** 5R01NS123285-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** YUE YANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $415,538
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442579

## Citation

> US National Institutes of Health, RePORTER application 10442579, Mechanisms of Genome Architecture Regulation in Motor Learning (5R01NS123285-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10442579. Licensed CC0.

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