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.
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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.
Oncotarget. 2015 Dec 04 [Epub ahead of print]
Vineet K Dhiman, Kristopher Attwood, Moray J Campbell, Dominic J Smiraglia
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA. , Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA. , Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA. , Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.