Co-expression analysis reveals gene cluster associated with methylation of enhancers and chromosomal instability under TP63 and TRIM29 regulation.

Prostate adenocarcinoma (PRAD) is the second most common cause of cancer-related deaths in men. In PRAD, high variability in DNA methylation and a high rate of large genomic rearrangements is often observed. To elucidate the reasons behind such high variance, we integrated DNA methylation, RNA-seq, and copy number alterations datasets from The Cancer Genome Atlas (TCGA) focusing on PRAD and subsequently employed weighted gene co-expression network analysis (WGCNA). Our results show that only a single cluster of co-expressed genes is associated with genomic and epigenomic instability. Within this cluster, TP63 and TRIM29 are key transcription regulators and are downregulated in PRAD. We revealed that TP63 regulates the level of enhancer methylation in prostate basal epithelium cells. TRIM29 forms a complex with TP63 and together regulate the expression of genes specific to the prostate basal epithelium. Moreover, TRIM29 binds DNA repair proteins and prevents formation of the TMPRSS2:ERG gene fusion typically observed in PRAD. Therefore, the study shows that TRIM29 and TP63 are important regulators maintaining the identity of the basal epithelium under physiological conditions. Finally, we uncover the role of TRIM29 in PRAD development.