(060) Epigenetic and Gene Expression Profiles in Non-Plaque Tissues from Men with Peyronie’s Disease

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Abstract Introduction Peyronie’s Disease (PD) can significantly impact sexual function. A hereditary predisposition to PD suggests that genetic variants may exist, and gene expression may modulate the penetrance of the disease. Identification of changes in epigenetic and gene expression profiles will facilitate a deeper understanding of the disease and provide insight for more targeted therapies. Objective Our objective is to determine if PD is correlated with epigenetic variations and/or gene expression changes, as indicated by DNA methylation assessment and RNA sequencing. Methods Penile tunica albuginea samples (not from fibrotic plaques) were obtained from men with PD undergoing penile prosthesis placement. Control samples were collected from men with erectile dysfunction (ED) without PD undergoing penile prosthesis placement. DNA methylation analyses were performed on homogenized penile tissue samples via an Illumina Human MethylationEPIC BeadChip v2 array. Using the minfi package in R, beta values were produced for all 936,990 CpG sites for each sample and SWAN normalization was applied. Differentially methylated regions (DMR) were found via USEQ with a threshold Wilcoxon FDR score of 40. Gene expression levels were examined in PD and ED samples via RNA-sequencing. Gene expression data was compared against epigenetic data to determine if any epigenetics changes identified affected gene expression profiles. Results A total of 24 tissue samples were collected: 12 ED and 12 PD. USEQ yielded 36 total DMRs with an FDR score of 40 or greater (p-value<0.0001). Of these 36 DMRs, a Stanford GREAT analysis revealed 60 total gene-region associations and five implicated biological processes: anterior/posterior pattern specification, chordate embryonic development, embryo development (ending in birth or egg hatching), somitogenesis, and pattern specification process. Furthermore, differential gene expression analysis identified 76 genes with significant expression changes between PD and ED groups, of which 17 genes were upregulated while 59 were downregulated. Long noncoding RNAs and the keratocan gene showed notable expression differences between PD and ED groups. GO enrichment analysis revealed significant terms related to DNA binding and protein binding. None of the differentially regulated genes overlapped with identified DMRs. Conclusions This study identified distinct gene expression and DNA methylation patterns between PD and ED groups, despite PD samples not being taken from plaque regions, suggesting that more systemic changes may be present. Upregulated genes in PD included long noncoding RNAs and the keratocan gene, suggesting their involvement in disease pathogenesis. Long noncoding RNA overexpression may serve a regulatory function in gene expression or cell processes while overexpression of the keratocan gene may promote collagen accumulation and remodeling, leading to fibrous plaque formation. Likewise, DMRs and their region-gene associations suggest a role in early embryonic development for pathogenesis. Although RNA-seq did not indicate any significant differentially expressed genes that matched with gene-region associations correlated with DMRs, the significance and quantity of DMRs between ED and PD sample groups is indicative of affected biological processes that manifest in distinct pathophysiologies. Further research is needed to investigate if differentially regulated genes exist in DMRs that exhibited changes but did not meet the criteria threshold for inclusion here. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Contraline, Techfields Inc, Alto Neurosciences, Curebase.