# Quiescent-induced transcriptional regulation

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $359,100

## Abstract

To survive, organisms must resist stress. Quiescence (or G0) is an adaptive response in which cells resist stress, enter a
reversible dormancy and remain viable for long periods of time. How cells enter, survive and exit G0 is a critical question
in basic biology, which is currently poorly understood. This is because for decades G0 was often deemed as an
`uneventful' state in the cell cycle; however, recent discoveries have challenged this dogma and underscored the
importance of G0 regulation in several human pathologies, including cancers. Therapeutic intervention requires a basic
understanding of how cells transition to and from G0 and the molecular switches that govern these processes.
Remarkably, these remain largely open questions in biology. G0 entry requires the establishment of a unique
transcriptional state, which imparts distinct properties to G0 cells. It is also concomitant with redistribution of
heterochromatic marks, suggesting that heterochromatin proteins contribute to G0 establishment.
 To address this knowledge gap, we recently modeled G0 in the fission yeast cells. G0 in S. pombe bears many
similarities to that in mammalian cells including inducing signals (nutrient depletion), long life, resistance to genotoxic
agents, lower metabolism, and use the same biological pathways (e.g. autophagy) and protein complexes (e.g.
proteasome). The major advantage of using fission yeast as a G0 model is that upon nitrogen starvation (or glucose
deprivation) all cells enter quiescence uniformly, creating pure, synchronous and isogenic populations of G0 cells. We
exploited these features and developed a time-course G0 assays to track cell viability, chromatin, transcriptional and small
RNA (sRNA) changes temporally. We found that as cells enter G0 a new class of Argonaute 1(Ago1)-associated small
RNAs (G0 sRNAs) emerges, which deploys constitutive heterochromatin proteins to euchromatic parts of the genome.
We showed that RNAi- and heterochromatin proteins are essential for survival and establishment of the G0 program.
Overall, we discovered a novel role for constitutive heterochromatin proteins (global regulation of transcription in G0)
and nuclear Ago1-associated sRNAs in adaptation to long-term stress. Based on these, we proposed a general model for
Quiescent-induced Transcriptional Silencing (QuieTS) in eukaryotes, in which early accumulation of sequence specificity
factors (e.g. G0 sRNAs) target the global deployment of regulatory proteins, under persistent stress. In this proposal, we
will determine how G0 sRNA are formed (Aim 1), and identify the complexes and the mechanisms which mediate
QuieTS (Aim 2). We will also test the generality of this mechanism as an adaptive response to long term stress and
delineate the core and stress-specific targets of QuieTS (Aim 3). Overall, the proposed studies will greatly impact our
understanding of the mechanisms by which G0 transcriptional programs are established and may reshape the current
models...

## Key facts

- **NIH application ID:** 10004145
- **Project number:** 5R01GM125782-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Mo Motamedi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $359,100
- **Award type:** 5
- **Project period:** 2017-09-15 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004145

## Citation

> US National Institutes of Health, RePORTER application 10004145, Quiescent-induced transcriptional regulation (5R01GM125782-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10004145. Licensed CC0.

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