# Project 1: Epigenetic Determinants of Muscle Stem Cell Aging

> **NIH NIH P01** · STANFORD UNIVERSITY · 2020 · $544,126

## Abstract

SUMMARY
 The loss of tissue regenerative capacity is an almost ubiquitous aspect of mammalian aging.
Underlying this age-related change is a decline in the potential of tissue-specific stem cells to
participate in tissue repair and regeneration. In skeletal muscle, this has been amply demonstrated for
the resident muscle stem cells (MuSCs), whose response to injury has been shown to decline with age
in response to cell-intrinsic changes and to suppressive activity from the aged systemic milieu, the
former perhaps arising from the latter. Nevertheless, the molecular basis of the cellular changes that
integrate these diverse inputs to render a MuSC less responsive with age remains to be determined.
Likewise, the molecular basis for the cellular memory that persists ex vivo and that can be
“reprogrammed” in vivo in response to different environments remain to be elucidated. Understanding
these fundamental mechanisms of MuSC aging provide the potential for being able to intervene to
restore youthful characteristics to aged stem cells, thus enhancing aged tissue repair and regeneration.
 Toward these goals, this Project focuses primarily on epigenetic mechanisms based on the
hypothesis that it is the epigenome that integrates diverse signals, mediates cellular responses, and is
amenable to reprogramming in response to diverse environmental influences. In collaboration with
Projects 2 and 3 and with Core C, we will explore the epigenetic features and regulators of young and
aged MuSCs, in terms of transcriptome (RNA-seq), epigenome (ChIP-seq), and nucleosome
positioning (ATAC-seq). In collaboration with Core B, we and Projects 2 and 3 will explore in more
detail the notion of “epigenetic rejuvenation” by studying the epigenetics of aged MuSCs (and other
stem cells) exposed to rejuvenating interventions that have been shown to restore youthful function to
aged stem cells. We will examine a specific histone mark, trimethylation of lysine 27 on histone 3
(H3K27me3) what we have shown previously to be strikingly enriched in aged MuSCs. We will examine
how that pattern changes in response to rejuvenating strategies and how it is regulated by chromatin
modifiers. In collaboration with Project 3, we will explore the role of DNA methylation in MuSC aging,
also testing how this epigenetic pattern, and resulting cellular function, changes in response to Core B
interventions and to alterations in expression of DNA demethylases. We will also use modified
CRISP/cas9 technology to modify DNA methylation in a locus-specific manner. Finally, in collaboration
with Project 2, we will explore the population dynamics of MuSC aging by using single cell RNA-seq
analysis to evaluate changes in clonal diversity and to test for clonal expansion, a process that we will
also explore independently using clonal lineage tracing strategies. We will work closely with all
members of this Program to integrate our efforts to lead the field of epigenetics of stem cell aging.

## Key facts

- **NIH application ID:** 9934979
- **Project number:** 5P01AG036695-09
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** THOMAS A. RANDO
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $544,126
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934979

## Citation

> US National Institutes of Health, RePORTER application 9934979, Project 1: Epigenetic Determinants of Muscle Stem Cell Aging (5P01AG036695-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9934979. Licensed CC0.

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