Imprecise DNMT1 activity coupled with neighbor-guided correction enables robust yet flexible epigenetic inheritance

Area of Science:

• Epigenetics
• Molecular Biology
• Genetics

Background:

• The epigenome, including DNA methylation, is crucial for stable inheritance during cell division.
• Single-cell clonal expansion can lead to methylome heterogeneity, posing a challenge to epigenetic stability.

Purpose of the Study:

• To investigate how DNA methylation patterns are maintained stably despite epigenetic drift.
• To understand the role of DNA (cytosine-5)-methyltransferase 1 (DNMT1) in epigenetic stability.

Main Methods:

• Generating base-resolution maps of DNMT1 activity.
• Analyzing methylome heterogeneity in clonal cell populations.
• Investigating epigenetic drift and correction mechanisms.

Main Results:

• DNMT1-only cells produce heterogeneous methylomes that are robustly propagated.
• DNMT1 exhibits imprecise maintenance and potential de novo activity, causing epimutations.
• A neighbor-guided mechanism, involving DNMT1's environment-sensitive activities, corrects these epimutations.
• H3K9me2/3-marked regions show increased de novo activity, while CpG islands exhibit poor maintenance and de novo activities.

Conclusions:

• Epigenetic machinery combines imprecise maintenance with neighbor-guided correction for robust yet flexible inheritance.
• DNMT1 plays a dual role in both introducing and correcting epigenetic variations.
• This mechanism is fundamental to epigenetic inheritance, balancing stability with adaptability.