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

Nature Genetics
Qiujun WangWei Xie

Abstract

The epigenome, including DNA methylation, is stably propagated during mitotic division. However, single-cell clonal expansion produces heterogeneous methylomes, thus 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 possibly possesses weak de novo activity, leading to spontaneous 'epimutations'. However, these epimutations tend to be corrected through a neighbor-guided mechanism, which is likely to be enabled by the 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.

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Citations

Dec 11, 2020·Nucleic Acids Research·Nataliya PetrykPierre-Antoine Defossez
Oct 29, 2020·Journal of Experimental & Clinical Cancer Research : CR·Tiansheng LiYongguang Tao
Feb 27, 2021·Developmental Cell·Yitzhak ReizelKlaus H Kaestner
Mar 28, 2021·Journal of Genetics and Genomics = Yi Chuan Xue Bao·Xuan MingYingfeng Li
Oct 24, 2020·Trends in Genetics : TIG·Hiten D Madhani
May 5, 2021·Nature Communications·Wendan RenJikui Song
Jun 19, 2021·Nature Structural & Molecular Biology·Chuck HaggertyAlexander Meissner
Jun 15, 2021·Trends in Genetics : TIG·Atsuya Nishiyama, Makoto Nakanishi
Oct 6, 2021·Nature Reviews. Genetics·Sanne M Janssen, Matthew C Lorincz

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Methods Mentioned

BETA
MethylC sequencing
MethylC-seq
immunoprecipitation
BS-seq
FCS
gene knockout
transfection
genotyping
FACS
dot blot

Software Mentioned

TopHat2
Tools
Bowtie
Image J
ZEN
R
Dispersion Shrinkage for Sequencing
UCSC Genome Browser
HBS
Cufflinks

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