# Functions and Mechanisms of Epigenetic Allelic Effects in the Brain

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

## Abstract

PROJECT SUMMARY
For reasons that are unclear, neuropsychiatric disorders are phenotypically variable and often the same gene
is implicated in different disorders. Our limited understanding of the link between genotype and phenotype has
stalled the development of improved diagnostics and therapeutics. An NIMH strategic priority to address this
involves deepening our understanding of regulatory factors that alter gene expression and are important for
brain processes relevant to mental illness. Little is known about allele-specific epigenetic effects that could
interact with heterozygous genetic mutations to influence phenotypic variance and mental health. The goal of
this study is to uncover novel epigenetic effects at the allele, protein and cellular level in the brain. In a
recent publication in Neuron, we uncovered thousands of genes that differentially express their maternal and
paternal alleles at the RNA level in vivo in a developmentally regulated manner in the mouse and primate
brain. We refer to these phenomena as differential allele expression effects (DAEEs). DAEEs are not due to
genetic variation or genomic imprinting and involve random monoallelic expression in subpopulations of brain
cells. We found that DAEEs interact with heterozygous mutations to cause mosaics of monoallelic brain cells
that differentially express mutant versus wildtype alleles at the RNA level. Currently, we do not know whether
DAEEs result in random monoallelic expression at the protein level and involve stable or dynamic allelic
expression states in a cell over time. Moreover, it is unclear when DAEEs arise during brain development,
whether specific cell types are consistently impacted for different genes and whether DAEEs can interact with
heterozygous mutations to shape phenotypic effects. Therefore, we propose an exploratory study that will
begin to address these important gaps in our knowledge and set the foundations for future functional
and mechanistic studies of DAEEs in shaping mental health. Aim 1 will determine the expression profiles
of DAEEs at the protein and cellular level in the brain for different functional classes of genes with distinct
developmental patterns of epigenetic allelic effects, revealing monoallelic and biallelic brain cell populations at
the protein level and testing for stable versus dynamic allelic states in individual cells. Aim 2 will identify
candidate autosomal genes with stable random monoallelic expression effects that shape the impact of
heterozygous mutations on specific behavioral and neurological phenotypes. Our study is significant
because it addresses fundamental gaps in our knowledge and will uncover novel stable and/or dynamic
epigenetic allelic effects on brain gene expression at the protein level. The results will lay foundations to test
specific functional models that are expected to reveal mechanisms by which gene regulation at the allele and
cellular level in the brain contributes to phenotypic variance and ris...

## Key facts

- **NIH application ID:** 9957132
- **Project number:** 5R21MH120468-02
- **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:** 2019-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957132

## Citation

> US National Institutes of Health, RePORTER application 9957132, Functions and Mechanisms of Epigenetic Allelic Effects in the Brain (5R21MH120468-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9957132. Licensed CC0.

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