Abstract
DNA methylation is an epigenetic modification that contributes to stable gene silencing by interfering with the ability of transcriptional regulators to bind to DNA. Recent findings have revealed that hormone stimulation of certain nuclear receptors induces rapid, dynamic changes in DNA methylation patterns alongside transcriptional responses at a subset of target loci, over time. However, the ability of androgen receptor (AR) to dynamically regulate gene transcription is relatively under-studied and its role in the regulation of DNA methylation patterns remains to be elucidated. Here we demonstrate in normal prostate cells that hormone stimulated AR activity results in dynamic changes in the transcription rate and DNA methylation patterns at the AR target genes, TIPARP and SGK1. Time-resolved chromatin immunoprecipitation experiments on the SGK1 locus reveals dynamic recruitment of AR and RNA Polymerase II, as well as the recruitment of proteins involved in the DNA demethylation process, TET1 and TDG. Furthermore, the presence of DNA methylation at dynamic regions inhibits protein binding and transcriptional activity of SGK1. These findings establish AR activity as a contributing factor to the dynamic regulation of DNA methylation patterns at target genes in prostate biology and infer further complexity involved in nuclear receptor mediation of transcriptional regulation.
Highlights
Androgens are steroid hormones which exert their biological effects through the androgen receptor, a liganddependent nuclear receptor that binds androgen response elements (AREs) in the DNA to regulate gene expression [1]
We have demonstrated that DHT stimulation of AR results in dynamic changes in the DNA methylation patterns at biologically active AREs
At select CpG sites, this dynamic methylation pattern occurs inversely in phase with dynamic changes of the transcriptional rate of target genes. These data show that dynamic changes in DNA methylation play a role in transcriptional regulation
Summary
Androgens are steroid hormones which exert their biological effects through the androgen receptor, a liganddependent nuclear receptor that binds androgen response elements (AREs) in the DNA to regulate gene expression [1]. Models of transcription illustrated a mechanism that assumed a static chromatin environment, wherein promoter DNA regulatory elements served as stationary platforms to which nuclear receptors and their respective co-regulators bound as stable protein complexes, where they initiated and activated gene transcription [4] Under this model, it was proposed that these large protein complexes would remain bound to the DNA to continuously regulate transcription for long periods, until stimulus was withdrawn [5]. Recent studies have contrasted this model, revealing that hormone-dependent transcription is a dynamic signaling process that requires the continuous cyclical recruitment and sequential release of nuclear receptors at DNA response elements [6]. These dynamics have only been reported in prostate cancer cells on the PSA locus, and the relevance of dynamic AR signaling to normal prostate biology remains unexplored
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