The epigenome, including DNA methylation, is stably propagated during mitotic division. However, single-cell clonal expansion produces heterogeneous methylomes, raising the question of how the DNA methylome remains stable despite constant epigenetic drift. Here, we report that a clonal population of DNA (cytosine-5)-methyltransferase 1 (DNMT1)-only cells produces a heterogeneous methylome, which is robustly propagated on cell expansion and differentiation. Our data show that DNMT1 has imprecise maintenance activity and likely possesses weak de novo activity, leading to spontaneous epimutations. However, these epimutations tend to be corrected through a neighbor-guided mechanism, ikely enabled by environment-sensitive de novo activity (tuner) and maintenance activity (stabilizer) of DNMT1. By generating base-resolution maps of de novo and maintenance activities, we find that H3K9me2/3-marked regions show enhanced de novo activity, and CpG islands have both poor maintenance and de novo activities. The imprecise epigenetic machinery coupled with neighbor-guided correction may be a fundamental mechanism underlying robust yet flexible epigenetic inheritance. SOURCE: Wei Xie (xiewei121@tsinghua.edu.cn) -  Tsinghua University

Pluto Bioinformatics

GSE116482: Imprecise DNMT1 activity coupled with neighbor-guided correction enables robust yet flexible epigenetic inheritance