# Mechanisms of Target of Rapamycin Complex 1 Dependent Epigenetic Regulation

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2024 · $308,000

## Abstract

Project Summary
Environmental nutrient availability and metabolism profoundly affects an individual’s health, while deregulation
of nutrient signaling contributes to many diseases, including cancer. Nutrient signaling and metabolism
regulate the epigenome to affect cellular phenotype and function, yet mechanisms explaining how nutrients
signal to the epigenome are lacking. Defining these mechanisms constitutes a critical scientific problem that is
essential to address. By defining these mechanisms, we will understand how nutrient exposures affect health,
and how aberrant nutrient signaling causes disease. The mechanistic target of rapamycin complex 1
(mTORC1) is an evolutionarily conserved nutrient activated signaling pathway. MTORC1 responds to diverse
nutrient and metabolic inputs to promote cell growth and proliferation, and it is deregulated in cancer and other
diseases. While mTORC1 is an emerging epigenetic regulator, how it signals to the epigenome is unknown. In
this project, we will use a yeast model to build on our previous successes to define these mechanisms. Herein,
we will test the overarching hypothesis that TORC1 signaling controls the chromatin binding of architectural
proteins and histone reader proteins that maintain viability during nutrient stress and regulate metabolic gene
expression. In Aim I, we will identify specific epigenetic pathways acting on histone H3 that promote binding of
high mobility group box (HMGB) proteins to chromatin to prevent cell death under nutrient stress conditions.
We then will define biochemically and genetically how non-chromatin bound HMGB proteins cause cell death
during TORC1 stress. Stressed human cells evict HMGB1 from chromatin to affect cytoplasmic metabolic
activities, initiate innate immune signaling and inflammation, and promote tumorigenesis. These yeast studies
will identify conserved epigenetic pathways that are critical for retaining HMGB1 on chromatin during mTORC1
stress to prevent such HMGB1-induced pathological effects. Aim II will use proteomic and genomic
approaches to define how yeast TORC1 represses conserved sirtuin histone deacetylase activity to regulate
histone reader chromatin binding and control mitochondrial metabolic transcription. We then will perform
mechanistic studies to assess how these histone reader proteins transcriptionally regulate metabolic gene
expression. By the project’s conclusion, we will have defined novel and conserved mechanisms used by
TORC1 to modify the epigenome, which prevent cell death during nutrient stress and regulate metabolic gene
transcription. These mechanisms will be directly relevant for understanding how human mTORC1 deregulation
alters the epigenome to cause disease.

## Key facts

- **NIH application ID:** 10874599
- **Project number:** 5R01GM138393-03
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Ronald Laribee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $308,000
- **Award type:** 5
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874599

## Citation

> US National Institutes of Health, RePORTER application 10874599, Mechanisms of Target of Rapamycin Complex 1 Dependent Epigenetic Regulation (5R01GM138393-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10874599. Licensed CC0.

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