Dynamics extracted from fixed cells reveal feedback linking cell growth to cell cycle

Area of Science:

• Cell biology
• Molecular biology
• Biophysics

Background:

• Cell size variation is a fundamental biological question.
• Previous experimental limitations have hindered understanding of cell size regulation.
• Inferring dynamic molecular rates from static cell populations is challenging.

Purpose of the Study:

• To introduce a novel method, ergodic rate analysis (ERA), for inferring molecular event rates from fixed cell populations.
• To apply ERA to study cell growth and cell size control.
• To identify mechanisms that constrain cell size variation.

Main Methods:

• Ergodic Rate Analysis (ERA): A method utilizing single-cell measurements of fixed steady-state populations.
• ERA infers molecular event rates by relating the number of cells in a state to the average transit time through that state.
• ERA enables calculation of time trajectories for various cellular features (e.g., phosphoprotein levels, cell mass) in fixed cells.

Main Results:

• ERA accurately infers molecular event rates, including cell growth rates.
• The study identified a size-discriminatory process occurring at the G1/S cell cycle transition.
• This process was found to actively decrease cell-to-cell size variation.

Conclusions:

• Ergodic Rate Analysis (ERA) provides a powerful new tool for studying dynamic cellular processes using fixed cell samples.
• A size-discriminatory mechanism at the G1/S transition plays a key role in maintaining uniform cell size.
• ERA opens new avenues for investigating cell size regulation and other molecular dynamics.