Epigenetic fluctuations underlie gene expression timescales and variability

Area of Science:

• Molecular Biology
• Genetics
• Epigenetics

Background:

• Isogenic mammalian cells display significant gene expression variability.
• Variability stems from cis-acting (allele-specific) and trans-acting (global) factors.
• Regulatory factor activity fluctuates across different timescales, impacting gene expression persistence.

Purpose of the Study:

• Investigate intrinsic, cis-regulatory factors causing slow gene expression variability.
• Isolate and measure allele-specific variability persistence.
• Identify the mechanisms behind slow, allele-specific gene expression fluctuations.

Main Methods:

• Developed a reporter system for allele-specific variability.
• Conducted imaging and long-term fluctuation analysis experiments.
• Employed mathematical modeling and direct assays of chromatin markers (H3K4me3).

Main Results:

• Identified a novel source of gene expression variability that is allele-specific and fluctuates over days.
• Demonstrated that allele-specific epigenetic factor fluctuations explain this variability.
• Observed H3K4me3 level fluctuations correlating with gene expression changes.

Conclusions:

• Slow fluctuations in regulatory chromatin modifications are a significant contributor to gene expression variability.
• The findings support a model where epigenetic dynamics drive slow, allele-specific gene expression changes.
• This work elucidates a new layer of gene expression regulation in mammalian cells.