# Measuring and perturbing metabolic rhythms and the cell division cycle in single cells

> **NIH NIH R01** · NORTH CAROLINA STATE UNIVERSITY RALEIGH · 2020 · $296,767

## Abstract

PROJECT ABSTRACT: Metabolic rhythms occur in different cells and compartments within organisms. The
origins and impact of these rhythms on other biological oscillators (e.g. cell cycle, circadian clocks) is only
starting to be understood. The applicant’s long-term goal is to understand the mechanisms, function, and
interaction of metabolic rhythms and the cell cycle in budding yeast, a model eukaryote. The yeast metabolic
cycle (YMC) is a synchronous metabolic rhythm that occurs in a chemostat. The population synchrony arises
from YMC-to-YMC coupling between cells via secreted metabolites. The YMC within each cell also interacts
with the cell division cycle (CDC) to coordinate the events of carbon catabolism and cell cycle entry. These two
oscillators have different periods, yet remain coordinated such that a fraction of the population commits to the
CDC each YMC. Inference of YMC-CDC dynamics has been challenging because metabolic and cell cycle
events are often measured and averaged across a heterogeneous population, which masks the dynamics that
occur in a single cell. The objective of this proposal is to obtain new insights into these intracellular oscillators
by measuring and perturbing the YMC and CDC in single cells. The central hypothesis is that the YMC and
CDC can oscillate independently of one another but are normally coordinated in yeast through a reinforcing
feedback loop (i.e., entry into a carbon catabolic state triggers the cell cycle, and, reciprocally, initiating the cell
cycle triggers entry into a carbon catabolic state). The applicants will generate data that address the central
hypothesis and its alternative with three specific aims: (1) Develop fluorescent reporter assays to measure
population snapshots of metabolic and cell cycle states in single cells taken from a cycling chemostat; (2)
Perturb the reinforcing feedback loop to disrupt the synchronization of YMC and CDC events in a cycling
chemostat; and (3) Measure and perturb YMC-CDC dynamics outside the chemostat using timelapse
fluorescence microscopy with microfluidics. Aim 1 will elucidate the timing and coordination of metabolic and
cell cycle events in a cycling chemostat across different growth conditions. Aim 2 will directly test the
reinforcing feedback loop that coordinates these oscillators in a cycling chemostat. Aim 3 will measure the
extent to which metabolic rhythms occur in the absence of cell-to-cell communication via secreted metabolites
and whether they remain coordinated with cell cycle events as seen in the chemostat. The observation that
carbon catabolism and cell cycle entry remain coordinated in single cells across diverse growth conditions
would strongly support the central hypotheses. This work is innovative because it combines single-cell
technology and molecular genetics to address an unsolved problem in yeast with broad relevance to metabolic
rhythms and cell cycle in other eukaryotes. This proposal is significant because it elucidates new me...

## Key facts

- **NIH application ID:** 9901540
- **Project number:** 5R01GM127614-04
- **Recipient organization:** NORTH CAROLINA STATE UNIVERSITY RALEIGH
- **Principal Investigator:** NICOLAS EMILE BUCHLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $296,767
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9901540

## Citation

> US National Institutes of Health, RePORTER application 9901540, Measuring and perturbing metabolic rhythms and the cell division cycle in single cells (5R01GM127614-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9901540. Licensed CC0.

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