# Single-Cell Analysis of Aging-Associated 4D Nucleome in the Human Hippocampus

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $607,049

## Abstract

Project Summary / Abstract
 Age-related cognitive decline is an important concern in the United States, as approximately 20% of the
US population is expected to be age 65 or older by year 2030. Understanding the molecular mechansims of
brain aging to prolong healthy cognitive function is therefore increasingly important as the population ages and
older people remain in the work force. Brain cells exhibit profound and heterogeneous changes during aging at
molecular and cellular levels. The simple intervention of physical exercise has emerged as a major positive
modulator of cognitive function in aging. In response to RFA-RM-20-005, we have formed an interdisciplinary
team with expertise in single-cell genomics, neural circuitry, and aging, to investigate age- and physical activity-
related changes of 4D nucleome in post-mortem human brain hippocampus cells across the lifespan with single-
cell resolution. We hypothesize that cell-type-specific re-organization of nucleome occurs in the human
hippocampal brain region during aging and with physical activity. The changes in nucleome in turn control brain
epigenome and transcriptome, modulating neural circuit functionality. The “Methyl-HiC”, a new approach for
joint profiling of DNA methylation and chromatin contacts in single cells, combined with “Paired-seq”, an ultra-
high-throughput method for single-cell joint analysis of open chromatin and transcriptome, will be used to
interrogate the chromatin architecture along with DNA methylation, chromatin accessibility and gene expression
in the human hippocampus. In Aim 1, we will determine changes in nucleome in major cell types of post-mortem
human hippocampus across the life-span with 4 age ranges (20–39, 40–59, 60–79, and 80–99 years old). We
will further correlate these changes in nucleome with epigenome and transcriptome in each cell type, to identify
vulnerable cell types during aging, and uncover potential gene regulatory programs that could be impacted by
aging. In Aim 2, we will determine how physical activity modifies and restores nucleome in specific human
hippocampal cell types. We will study two age-matched cognitively–healthy cohorts (70-99 years old) with either
high level or low level physical activity, as measured by wearable activity monitors. We will correlate restorative
effects on nucleome with epigenome and transcriptome. In Aim 3, we will map how aging and exercise alter
nucleome in specific hippocampal cell types with highly controlled quantifiable physical activity in the mouse
model, for comparison with human data. These mouse studies allow the exercise variable to be investigated in
isolation from effects of other lifestyle factors that can affect hippocampal nucleome, which is not possible with
human subjects. The proposed research will help to transform our ability to understand the mechanisms of
chromatin organization and function in the context of human brain aging.

## Key facts

- **NIH application ID:** 10267725
- **Project number:** 5U01DA052769-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Carl Wayne Cotman
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $607,049
- **Award type:** 5
- **Project period:** 2020-09-30 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10267725

## Citation

> US National Institutes of Health, RePORTER application 10267725, Single-Cell Analysis of Aging-Associated 4D Nucleome in the Human Hippocampus (5U01DA052769-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10267725. Licensed CC0.

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