# Project 1: Epigenetic control of cell identity and inflammation in aging

> **NIH AG P01** · UNIVERSITY OF PENNSYLVANIA · 2026 · $401,405

## Abstract

SUMMARY
The epigenome and transcriptome determine cell identity and function. In liver, transcriptional regulator Hnf4α
contributes to hepatocyte identity. We found that aging results in decreased expression of highly expressed
Hnf4α target genes, suggestive of loss of cell identity. The cause and consequence of loss of cell identity and
whether its reversal can be an intervention for healthy aging is not well understood.
 This PPG has predicted that to maintain their identity over the lifespan cells possess chromostasis
mechanisms that maintain integrity of the dynamic epigenome, retard chromatin change and hence maintain
healthy cell identity, tissue phenotype and function. As a potential chromostasis mechanism, in non-dividing
cells, such as liver hepatocytes, histone variant H3.3 accumulates with age. Hira is a DNA replication
independent histone chaperone that deposits histone H3.3 into nucleosomes, especially at active gene bodies,
promoters and enhancers. Recently, we found that inactivation of Hira specifically in mouse liver hepatocytes
causes downregulation of highly expressed Hnf4α target genes, apparent loss of hepatocyte identity and
transcriptomic, metabolic and inflammatory dysfunction of aging liver. The mechanism by which age-dependent
deposition of histone H3.3 preserves cell identity and whether this can be targeted for healthy aging is unknown.
 Accumulation of senescent cells in aged tissues also contributes to tissue aging, in part via pro-
inflammatory Senescence-Associated Secretory Phenotype (SASP). This PPG previously showed that
senescent cells expel chromatin from the nucleus into the cytoplasm, generating cytoplasmic chromatin
fragments (CCF). CCF are sensed by the cytoplasmic cGAS/STING pathway, thereby activating NFκB and
SASP. Our previous and ongoing studies showed that in senescent cells, HIRA localizes to PML nuclear bodies,
and that both HIRA and PML, in conjunction with autophagy regulator p62SQSTM1 (p62), control activation of
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## Key facts

- **NIH application ID:** 11096619
- **Project number:** 1P01AG092325-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** PETER D. ADAMS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** AG
- **Fiscal year:** 2026
- **Award amount:** $401,405
- **Award type:** 1
- **Project period:** 2026-02-01T00:00:00 → 2031-01-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11096619

## Citation

> US National Institutes of Health, RePORTER application 11096619, Project 1: Epigenetic control of cell identity and inflammation in aging (1P01AG092325-01). Retrieved via AI Analytics 2026-07-04 from https://api.ai-analytics.org/grant/nih/11096619. Licensed CC0.

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