# Stochastic tuning: a novel regulatory mechanism for cellular adaptation

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $402,442

## Abstract

Abstract
Regulation of gene expression is the fundamental mechanism by which cells adapt to changes in the external
environment. As such, dedicated pathways have evolved to sense environmental signals and to convey this
information to specific signaling and regulatory circuits in order to execute pre-programmed changes in gene
expression. This has been our conventional understanding of gene regulation and cellular adaptation for over
sixty years. We have recently discovered that eukaryotic cells employ an entirely distinct strategy to achieve
adaptive gene expression states independent of these conventional hard-wired pathways. In this process that
we call stochastic tuning, cells utilize the inherent noise in mRNA transcription to randomly increase or
decrease expression of genes and to actively reinforce only those changes that improve the overall health of
the cell. This real-time empirical optimization strategy enables cells to adapt to extreme/unfamiliar
environments by establishing arbitrary patterns of gene expression that are beyond the capacity of their hard-
wired regulatory programs. We have extensive published and preliminary data that stochastic tuning operates
in both budding yeast S. cerevisiae and human cell-lines. We are compelled by the possibility that stochastic
tuning may be a widespread mechanism of adaptation in eukaryotes. In particular, it may be the basis for ‘non-
genetic’ phenomena of disease relevance including epigenetic chemotherapeutic resistance. We have recently
identified candidate genetic loci and chemical perturbations that substantially affect stochastic tuning behavior
in yeast. We propose to substantially scale these efforts to comprehensively identify the underlying cis and
trans molecular effectors using unbiased systems biological approaches. These include: (1) utilization of our
recently developed full yeast CRISPR-interference library to quantitatively determine the role of all essential
and non-essential genes in stochastic tuning; (2) Comprehensive profiling of all core yeast promoters for tuning
efficacy using FACS-sorting of fluorescent reporter libraries and high-throughput sequencing; (3) de novo
computational inference and experimental validation of critical DNA sequence features; (4) high-resolution
profiling of mRNA and chromatin dynamics along a tuning trajectory; (5) precise induction and monitoring of
tuning events using optogenetic perturbations and high-temporal resolution monitoring of gene expression in
single cells; and (6) determining the functional roles of discovered effectors in the distinct phases of tuning
using a closed-loop system that enables precise control and monitoring of tuning trajectories. These efforts
represent the very first systematic genetic interrogation of stochastic tuning. We expect these studies to
generate a parts-list of key effectors in stochastic tuning and to delineate their roles in the various phases of
the process, monitored and perturbed in single cel...

## Key facts

- **NIH application ID:** 10453580
- **Project number:** 5R01GM139215-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Saeed F Tavazoie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,442
- **Award type:** 5
- **Project period:** 2020-09-09 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10453580

## Citation

> US National Institutes of Health, RePORTER application 10453580, Stochastic tuning: a novel regulatory mechanism for cellular adaptation (5R01GM139215-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10453580. Licensed CC0.

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