# Molecular mechanisms of cellular response to age-associated chromatin changes

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $336,000

## Abstract

PROJECT SUMMARY
 Profound changes in chromatin occur in aged cells and tissues. These changes, such as altered histone
modifications and chromatin conformation, lead to loss of heterochromatin, reduced nucleosome stability, and
aberrant transcription, all of which have been causally linked to the aging process. Using yeast strains with
reduced histone dosage, a model mimicking the situation of aged cells, we uncovered a cellular response to
such chromatin defects, named chromatin architectural defects (CAD) response or simply chromatin stress
response. Like cellular stress to heat and oxidation where moderate levels of stress can lead to hormesis, a
beneficial effect, activating CAD response with moderate chromatin defects extends lifespan, offering a new
intervention strategy to antagonize aging and age-related diseases. However, many mechanistic details of this
response remain unexplored. This project will focus on these mechanistic questions. Does the CAD response
directly mitigate age-associated chromatin changes and defects, such as disrupted heterochromatin, loss of
transcription silencing and cryptic transcription? TOR inhibition is critical for the longevity effect of CAD response.
How does the CAD response crosstalk with other TOR-related stress response pathways? In particular, does
the CAD response interact with Isw2-regulated longevity-promoting stress responses? How does CAD response
interact with metabolic changes? What are the regulators and effectors of CAD response? Importantly, how does
the previously identified CAD response transcription factor Gis1 function to activate the transcriptional response?
Addressing these questions pertaining to detailed molecular mechanisms will help characterize CAD response
with molecular regulators and effectors, physiological effects to the cell, and relationships with other stress
response and metabolic pathways. These mechanistic details will establish CAD response as a novel form of
stress response with hormetic effects that promote longevity.

## Key facts

- **NIH application ID:** 10816466
- **Project number:** 5R01AG081347-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Weiwei Dang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $336,000
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10816466

## Citation

> US National Institutes of Health, RePORTER application 10816466, Molecular mechanisms of cellular response to age-associated chromatin changes (5R01AG081347-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10816466. Licensed CC0.

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