Oestrogen receptor β regulates epigenetic patterns at specific genomic loci through interaction with thymine DNA glycosylase

Abstract

BackgroundDNA methylation is one way to encode epigenetic information and plays a crucial role in regulating gene expression during embryonic development. DNA methylation marks are established by the DNA methyltransferases and, recently, a mechanism for active DNA demethylation has emerged involving the ten-eleven translocator proteins and thymine DNA glycosylase (TDG). However, so far it is not clear how these enzymes are recruited to, and regulate DNA methylation at, specific genomic loci. A number of studies imply that sequence-specific transcription factors are involved in targeting DNA methylation and demethylation processes. Oestrogen receptor beta (ERβ) is a ligand-inducible transcription factor regulating gene expression in response to the female sex hormone oestrogen. Previously, we found that ERβ deficiency results in changes in DNA methylation patterns at two gene promoters, implicating an involvement of ERβ in DNA methylation. In this study, we set out to explore this involvement on a genome-wide level, and to investigate the underlying mechanisms of this function.ResultsUsing reduced representation bisulfite sequencing, we compared genome-wide DNA methylation in mouse embryonic fibroblasts derived from wildtype and ERβ knock-out mice, and identified around 8000 differentially methylated positions (DMPs). Validation and further characterisation of selected DMPs showed that differences in methylation correlated with changes in expression of the nearest gene. Additionally, re-introduction of ERβ into the knock-out cells could reverse hypermethylation and reactivate expression of some of the genes. We also show that ERβ is recruited to regions around hypermethylated DMPs. Finally, we demonstrate here that ERβ interacts with TDG and that TDG binds ERβ-dependently to hypermethylated DMPs.ConclusionWe provide evidence that ERβ plays a role in regulating DNA methylation at specific genomic loci, likely as the result of its interaction with TDG at these regions. Our findings imply a novel function of ERβ, beyond direct transcriptional control, in regulating DNA methylation at target genes. Further, they shed light on the question how DNA methylation is regulated at specific genomic loci by supporting a concept in which sequence-specific transcription factors can target factors that regulate DNA methylation patterns.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0055-7) contains supplementary material, which is available to authorised users.

Supraphysiological estradiol level in ovarian stimulation cycles affects the birthweight of neonates conceived through subsequent frozen‐thawed cycles: a retrospective study

“…The methylation and expression of imprinted regions have been linked with the phenotypes of fetal growth, which were suggested to contribute to the developmental programming of chronic disease in adulthood . It has been shown that estrogen receptors may regulate epigenetic patterns at specific genomic loci or interact with components of methylation mechanisms . The body of evidence warrants a concern regarding the long‐term health risks of individuals whose key stages of epigenetic programming are exposed to supraphysiological estradiol.…”

Active DNA demethylation by DNA repair: Facts and uncertainties

“…Moreover, cyclical fluctuations of gene promoter methylation were observed upon transcriptional stimulation by nuclear and hormone receptors [119,120]. Intriguingly, the gene activation accompanied by an overall reduction of DNA methylation was shown to engage DNMTs, Gadd45a, TET and BER proteins such as APE1, DNA polymerase β and TDG [119][120][121][122][123][124][125]. All these observations hint to a functional interplay between DNA methylation and demethylation processes to provide locus-specific epigenetic plasticity that allows post-developmental somatic cells to regulate transcriptional activity in response to environmental and systemic cues.…”

Pregnancy Reprograms Large-Conductance Ca 2+ -Activated K + Channel in Uterine Arteries

“…58–60 Additionally, estrogen could facilitate active demethylation by targeting TDG to the hypermethylated site via activation of ERβ. 61 Passive demethylation, occurring due to loss of maintenance methylation activity conferred by DNMTs, may also contribute to relieving gene repression. 62, 63 The potential involvement of passive demethylation in regulating KCNMB1 expression in pregnancy could not be excluded and merits further investigation.…”