TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers.

Nature Genetics
Jocelyn CharltonAlexander Meissner

Abstract

Mammalian cells stably maintain high levels of DNA methylation despite expressing both positive (DNMT3A/B) and negative (TET1-3) regulators. Here, we analyzed the independent and combined effects of these regulators on the DNA methylation landscape using a panel of knockout human embryonic stem cell (ESC) lines. The greatest impact on global methylation levels was observed in DNMT3-deficient cells, including reproducible focal demethylation at thousands of normally methylated loci. Demethylation depends on TET expression and occurs only when both DNMT3s are absent. Dynamic loci are enriched for hydroxymethylcytosine and overlap with subsets of putative somatic enhancers that are methylated in ESCs and can be activated upon differentiation. We observe similar dynamics in mouse ESCs that were less frequent in epiblast stem cells (EpiSCs) and scarce in somatic tissues, suggesting a conserved pluripotency-linked mechanism. Taken together, our data reveal tightly regulated competition between DNMT3s and TETs at thousands of somatic regulatory sequences within pluripotent cells.

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Citations

Oct 8, 2020·Nature Reviews. Genetics·Aled ParryWolf Reik
Dec 11, 2020·Nucleic Acids Research·Nataliya PetrykPierre-Antoine Defossez
Jan 10, 2021·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Natsuki TakamuraKunihiro Ohta
Nov 6, 2020·Stem Cells International·Dan ZhouWei Du
Feb 2, 2021·Frontiers in Cell and Developmental Biology·Nikolas James TsiouplisAgeliki Tsagaratou
Feb 5, 2021·Frontiers in Cell and Developmental Biology·Vera Garcia-OuteiralDiana Guallar
Feb 27, 2021·Developmental Cell·Yitzhak ReizelKlaus H Kaestner
Mar 28, 2021·Journal of Genetics and Genomics = Yi Chuan Xue Bao·Xuan MingYingfeng Li
May 11, 2021·The Journal of Experimental Medicine·Jung-Yeon LimMinji Byun
Apr 28, 2021·Nature Reviews. Genetics·Edward Saehong Oh, Art Petronis
Nov 26, 2021·Immunological Reviews·Heng-Yi ChenChan-Wang Jerry Lio
Dec 8, 2021·Leukemia·Elisabeth R WilsonDavid H Spencer

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Methods Mentioned

BETA
WGBS
immunoprecipitation
transfection
by
genotyping
Ligation Sequencing
PCR
restriction digest
FACS
Illumina sequencing

Software Mentioned

Nanopolish
Homer
BSMAP
HBS
BedTools
Genome
Nanopype
browser
Homer findMotifsGenome
IGV

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