Effect of genomic and cellular environments on gene expression noise

Area of Science:

• Single-cell genomics
• Gene expression regulation
• Epigenetics

Background:

• Individual cells exhibit significant cell-to-cell variation in gene expression, known as noise.
• Genomic location and cellular environment are key sources of this expression noise.
• Existing methods lack the ability to map how expression noise varies across the genome.

Purpose of the Study:

• To develop a novel method for simultaneously measuring reporter gene expression noise and transcriptome-wide mRNA profiles in single cells.
• To conduct the first genome-wide survey of how genomic location influences gene expression noise.
• To differentiate intrinsic and extrinsic components of gene expression noise and link them to cellular states.

Main Methods:

• Developed and applied Single-cell Analysis of Reporter Gene Expression Noise and Transcriptome (SARGENT).
• Performed a comprehensive genome-wide survey of reporter gene integration sites.
• Quantified gene expression noise and analyzed associated mRNA profiles to identify regulatory factors.

Main Results:

• Identified distinct correlations between mean expression, expression noise, and specific histone modifications.
• Quantified intrinsic and extrinsic noise components, assigning the extrinsic component to stem-like versus differentiated cell states.
• Revealed that transgene integrations can influence endogenous gene expression, aiding in the identification of safe-harbor loci.

Conclusions:

• SARGENT is a powerful tool for measuring gene expression mean and noise genome-wide at single-cell resolution.
• The method provides novel insights into the regulation of gene expression noise across the entire genome.
• Findings facilitate the search for genomic safe-harbor loci and deepen the understanding of gene expression variability.