Abstract
Understanding the epigenetic control of normal differentiation programs might yield principal information about critical regulatory states that are disturbed in cancer. We utilized the established non-malignant HPr1-AR prostate epithelial cell model that upon androgen exposure commits to a luminal cell differentiation trajectory from that of a basal-like state. We profile the dynamic transcriptome associated with this transition at multiple time points (0 h, 1 h, 24 h, 96 h), and confirm that expression patterns are strongly indicative of a progressive basal to luminal cell differentiation program based on human expression signatures. Furthermore, we establish dynamic patterns of DNA methylation associated with this program by use of whole genome bisulfite sequencing (WGBS). Expression patterns associated with androgen induced luminal cell differentiation were found to have significantly elevated DNA methylation dynamics. Shifts in methylation profiles were strongly associated with Polycomb repressed regions and to promoters associated with bivalency, and strongly enriched for binding motifs of AR and MYC. Importantly, we found that dynamic DNA methylation patterns observed in the normal luminal cell differentiation program were significant targets of aberrant methylation in prostate cancer. These findings suggest that the normal dynamics of DNA methylation in luminal differentiation contribute to the aberrant methylation patterns in prostate cancer.
Highlights
HypermethylatedNES = 2.67 FDR = 5.7e-4Enrichment Score Enrichment ScoreNES = 2.54 FDR = 5.7e-4 HypomethylatedPolycomb Promoter Transcribed Bivalent Promoter Active Enhancer Poised Enhancer EnrichedHypermethylation HypomethylationBoth NS variation as a ranking parameter, as luminal cell specific genes were amongst the most enriched gene sets for DNA methylation dynamics (Fig. 2D, Supplementary Table S3, Supplementary Fig. S3).Dynamic methylation enriches for polycomb repressed regions and transcription factor binding.we sought to characterize the functional genome associated with androgen induced methylation dynamics
Differential expression significantly aligned with gene sets that define human basal and luminal epithelial cells in the human prostate[4], with the most upregulated genes strongly enriched for expression patterns specific to the luminal cells of human prostate (Fig. 1C,D)
Utilizing ChromHMM defined chromatin state profiles previously generated in non-malignant prostate epithelial cells (PrEC)[13], we observed significant enrichment for annotated dynamic methylation positions (DMPs) within Polycomb repressed regions, as well as in promoter regions associated with bivalency (Fig. 3A)
Summary
Utilizing ChromHMM defined chromatin state profiles previously generated in non-malignant prostate epithelial cells (PrEC)[13], we observed significant enrichment for annotated DMPs within Polycomb repressed regions, as well as in promoter regions associated with bivalency (Fig. 3A). This was true for both hypermethylated and hypomethylated sites as proportions between DMP groups were not substantially different. We detected strong enrichment for gene sets associated with Polycomb complex regulation (e.g. BENPORATH_PRC2_TARGETS) as well as it’s functional mark H3K27me[3] (e.g. MIKKELSON_ES_WITH_ H3K27ME3) in GSEA of TSS region methylation variance (Fig. 3B, Supplementary Fig. S3), further supporting the observed genomic distributions of DMPs in Polycomb repressed regions. Simultaneous enrichments for genes associated with H3K4me[3] (e.g. MIKKELSON_ES_LCP_WITH_H3K4ME3) are supportive of DMPs association with regions of bivalency
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