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

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.

Epigenomics and transcriptomics of systemic sclerosis CD4+ T cells reveal long-range dysregulation of key inflammatory pathways mediated by disease-associated susceptibility loci

“…Nevertheless, although we observed significant changes in DNA methylation and gene expression, in SSc CD4+ T cells, we cannot conclusively speculate on the effects these alterations have in regard to chromatin accessibility and structure without further validation in patients. However, previous studies do show a direct correlation between DNA methylation and chromatin states [86][87][88]; therefore, it is possible that chromatin structure is also altered in SSc CD4+ T cells.…”

TET-Mediated Epigenetic Regulation in Immune Cell Development and Disease

“…TET1 seems to exclude DNMT3A1, the longer isoform of DNMT3A, from proximal promoters and canyons where TET1 seems to preferentially bind in embryonic stem cells (Gu et al, 2018 ). Moreover, it was shown that TET proteins compete with DNMT proteins to regulate the methylation status of enhancers (Verma et al, 2018 ; Charlton et al, 2020 ).…”

Epigenetic Regulation of Dental Pulp Stem Cell Fate

“…The latter requires the involvement of ten-eleven translocation proteins (TET1, TET2, and TET3) and the activation-induced deaminase [ 22 ]. DNA methylation leads to gene silencing by arresting the binding of transcriptional factors or by chromatin remodeling, and its dynamics is involved in diverse biological processes [ 23 – 25 ]. Thus, DNA methylation plays a vital part in stem cell differentiation, development, and disease by regulating genes [ 26 – 28 ].…”