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Background  Overexpression of ERG transcription factor due to genomic  ERG -rearrangements defines a separate molecular subtype of prostate tumors. One of the consequences of ERG accumulation is modulation of the cell’s gene expression profile. Tudor domain-containing protein 1 gene ( TDRD1 ) was reported to be differentially expressed between  TMPRSS2:ERG -negative and  TMPRSS2:ERG -positive prostate cancer. The aim of our study was to provide a mechanistic explanation for the transcriptional activation of  TDRD1  in ERG rearrangement-positive prostate tumors.    Methodology/Principal Findings  Gene expression measurements by real-time quantitative PCR revealed a remarkable co-expression of  TDRD1  and  ERG  (r 2  = 0.77) but not  ETV1  (r 2 <0.01) in human prostate cancer  in vivo . DNA methylation analysis by MeDIP-Seq and bisulfite sequencing showed that  TDRD1  expression is inversely correlated with DNA methylation at the  TDRD1  promoter  in vitro  and  in vivo  (ρ = −0.57). Accordingly, demethylation of the  TDRD1  promoter in  TMPRSS2:ERG -negative prostate cancer cells by DNA methyltransferase inhibitors resulted in  TDRD1  induction. By manipulation of  ERG  dosage through gene silencing and forced expression we show that ERG governs loss of DNA methylation at the  TDRD1  promoter-associated CpG island, leading to  TDRD1  overexpression.    Conclusions/Significance  We demonstrate that ERG is capable of disrupting a tissue-specific DNA methylation pattern at the  TDRD1  promoter. As a result,  TDRD1  becomes transcriptionally activated in  TMPRSS2:ERG -positive prostate cancer. Given the prevalence of ERG fusions,  TDRD1  overexpression is a common alteration in human prostate cancer which may be exploited for diagnostic or therapeutic procedures.

ERG Induces Epigenetic Activation of Tudor Domain-Containing Protein 1 (TDRD1) in ERG Rearrangement-Positive Prostate Cancer