# Allelic regulatory mechanisms in the brain

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $190,625

## Abstract

PROJECT SUMMARY
For reasons that are not well understood, brain disorders are highly phenotypically variable and often the same
gene is implicated in different disorders. To address these challenges, a deeper understanding of the
mechanisms that regulate brain gene expression and brain cell development are required to set the stage for
preventative interventions and personalized outcome prediction and therapies. Interactions between genetic and
epigenetic effects could play important roles in shaping phenotypic variance and risk. In a recent paper in Neuron,
we uncovered epigenetic allele-specific expression effects in the mouse, macaque and human brain. The data
indicate that hundreds of genes differentially express their maternal and paternal alleles in vivo in a
developmentally regulated manner; we refer to these effects as differential allele expression effects (DAEEs).
DAEEs are not due to genetic variation or genomic imprinting, and involve random monoallelic expression at the
cellular level. We show that DAEEs interact with heterozygous mutations to cause mosaics of monoallelic brain
cells that differentially express mutant versus wildtype alleles. The results reveal a new layer of gene regulation
at the allele and cellular level that can shape genetic architecture.
 Currently, we do not know the mechanistic basis of DAEEs in the brain. Here, we will test the hypothesis
that DAEEs are caused by allele-specific inter- and intra- chromosomal regulatory contacts in the
genome of brain cells. 3D genomic regulatory architecture has important roles in gene regulation and changes
developmentally, but little is known about 3D regulatory architecture at the allele level in vivo in the brain. In Goal
1.1, we test whether DAEEs involve allele-specific regulatory contacts in the genome. This study will uncover
new regulatory architecture at the allele level in the brain that could improve our understanding of the
mechanisms causing phenotypic variance. In Goal 1.2, we will independently validate allelic regulatory contacts
using double 3D Fluorescent In Situ Hybridization (FISH) in primary mouse brain cells. This study will
independently confirm random monoallelic contact events in single brain cells. Overall, we expect to uncover the
mechanistic basis of DAEEs and novel allele-specific features of gene regulation in the mouse brain genome.
The results will set the foundation for future functional studies, and improve our understanding of how allele-
specific epigenetic effects can arise in vivo and could influence phenotypic variance and brain disorder risks.

## Key facts

- **NIH application ID:** 9820734
- **Project number:** 5R21MH118570-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Christopher Gregg
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $190,625
- **Award type:** 5
- **Project period:** 2018-12-01 → 2020-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9820734

## Citation

> US National Institutes of Health, RePORTER application 9820734, Allelic regulatory mechanisms in the brain (5R21MH118570-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9820734. Licensed CC0.

---

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