# New roles for REST during brain maturation

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $521,456

## Abstract

Despite advances in model systems for identifying genes involved in aging, many unanswered questions
still remain about the biology and underlying mechanisms in humans, particularly related to age-related
cognitive decline. This is, in part, because even between mouse and human genomes, genetic regulatory
elements have diverged, in sequence, numbers, and their presence in different genes. Additionally, the
extreme heterogeneity of cell types in brain is a factor. In this grant, we take on the challenging problem of
genetic mechanisms underlying human brain aging. First, we exploit the accumulated wealth of
knowledge of the transcriptional repressor, REST, to fully characterize its function in neurons in adult
brain. We, and others, have been studying REST for decades as a model for understanding fundamentals
of gene regulation because of some prominent features. REST has an easily recognizable unusually large
binding site that occurs in thousands of neuronal genes and it robustly signals its function when bound to
genes by recruiting chromatin modifiers. While others have reported an activator function for REST in
neurons, we have only found repressor function, so we will also settle this discussion in Aim 1. Aim 1 also
includes studies to identify “orphan” REST binding sites of unknown function. The results from this aim will
expand the neuronal functions under REST control, as well as provide a potentially new model of
repressor function, generally. Second, our preliminary results indicate REST is expressed to different
levels in different neuronal types, human and mouse, and that its loss in mice results in differential
transcriptional effects in these neurons. This parsing of REST function in human neurons is studied in
depth in Aims 2 and 3. We recently found that REST protein levels in human hippocampus increase with
age sometime in the second decade after birth, remaining elevated even in centenarians, whereas REST
levels in mouse brain are greatly reduced by 4-6m after birth, and stay extremely low for life, suggesting
human-specific REST functions and/or target genes with age. We will identify REST functions with age in
Aim 2. Third, polymorphisms in REST have been associated with the age-related disease, Alzheimer's
Disease (AD). A recent study suggests that REST is involved directly in cognitive decline, although some
of the published findings are at odds with our results. We will test hypotheses regarding REST gene
regulation in AD in Aim 3. In total, our proposed experiments will provide new information on REST
function and its potential impact on neuronal gene expression and chromatin changes during brain aging
and related pathologies. The experiments will also provide new information on fundamental questions
regarding repressor function.

## Key facts

- **NIH application ID:** 10164872
- **Project number:** 5R01NS099374-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Gail Mandel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $521,456
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10164872

## Citation

> US National Institutes of Health, RePORTER application 10164872, New roles for REST during brain maturation (5R01NS099374-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10164872. Licensed CC0.

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