Uncoupling gene expression noise along the central dogma using genome engineered human cell lines

Area of Science:

• Molecular Biology
• Systems Biology
• Genetics

Background:

• Eukaryotic protein synthesis is inherently stochastic, leading to gene expression noise.
• Variations in cellular content and thermodynamic fluctuations contribute to this noise.
• Identical cells in the same environment show differing protein abundances.

Purpose of the Study:

• To quantify the contribution of each step in protein synthesis to gene expression noise.
• To elucidate the underlying sources of gene expression noise.
• To develop a framework for approximating intrinsic and extrinsic noise.

Main Methods:

• Utilized CRISPR to engineer custom circuits in human cells.
• Uncoupled gene expression at transcriptional, translational, and post-translational levels.
• Employed an unbalanced two-reporter system to analyze noise.

Main Results:

• Decomposition of noise revealed transcription as the major source of intrinsic fluctuations.
• Coupling genes along the central dogma caused fluctuations to propagate.
• Accumulation of fluctuations led to increased global correlation between gene products.

Conclusions:

• Transcription is the dominant contributor to intrinsic gene expression noise.
• Interconnectedness of gene expression steps amplifies noise propagation.
• Understanding noise sources is crucial for controlling gene expression variability.