# Mechanisms of Genome Organization in Brain Development and Behavior

> **NIH NIH U01** · NORTHWESTERN UNIVERSITY · 2022 · $474,614

## Abstract

Project Summary
The long-term goals of the proposed research are to elucidate mechanisms of three-dimensional genome
architecture in the control of neuronal connectivity in the brain. It has recently been found that physiological
stimuli including sensory experience or developmental signals remodel neuronal genome architecture in vivo.
Strikingly, it's found that long-distance genome interactions massively increase in the developing
cerebellum in mice. The discovery of these long-distance interactions formed between genes critical for
neuronal differentiation unveils novel nuclear mechanisms by which genome architecture may play a role in the
wiring of the brain. These findings raise fundamental questions on the mechanisms and biological functions of
these interactions in the brain, which will be addressed in this grant. First, the organizing principles of
long-distance genome interactions in the brain will be elucidated. Based on the in vivo findings, the
hypothesis that long-distance genomic interactions are organized by specific epigenetic and
transcriptional features will be tested. In addition, the study will also test the hypothesis that
anchors of long-distance interactions assemble into higher-ordered subnuclear structures including
nuclear speckles or Mediator condensates, which function as transcriptionally active hubs. Second, the
projcet will define mechanisms by which long-distance interactions are formed in development. The BAF
chromatin remodeling complex alters the genome environment to activate or repress transcription and is
required for brain development in mice and humans, and its dysregulation results in human
neurodevelopmental disorders, including Coffin–Siris syndrome and autism. Based on our preliminary
findings, the hypothesis that the BAF complex transiently inhibits formation of long-distance genome
interactions in immature neurons of the developing brain will be tested. Following early development, the
inhibition of the long-distance interactions might be relieved by the recruitment of specific sets of
transcription factors that drive terminal neuron differentiation. This project will test the hypothesis that these
transcription regulators, identified using DNA motif analyses, promote the formation of the long-distance
genome interactions. Finally, this study will also test the hypothesis that the formation of long-distance
genome interactions is necessary for the maturation of neurons in vivo, including making proper
connections with their pre- and post-synaptic partners. The proposed research is significant as it will
advance our understanding of the mechanisms regulating genome architecture to control
neuronal differentiation in mammalian brain. Furthermore, these studies will provide an integrated view
on how genome folding in the nucleus orchestrates the assembly of neural circuits underlying behavior.

## Key facts

- **NIH application ID:** 10465187
- **Project number:** 5U01DA053691-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Tomoko Yamada
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $474,614
- **Award type:** 5
- **Project period:** 2020-09-30 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465187

## Citation

> US National Institutes of Health, RePORTER application 10465187, Mechanisms of Genome Organization in Brain Development and Behavior (5U01DA053691-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10465187. Licensed CC0.

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