Dynamic patterns of DNA methylation in the normal prostate epithelial differentiation program are targets of aberrant methylation in prostate cancer [Methyl Capture]

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 (0hr, 1hr, 24hr, 96hr), 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). HPr1-AR cells exposed to DHT (10nM) for 0, 1, 24 and 96 hours were analyzed by TruSeq Methyl Capture sequencing. Raw sequencing reads were aligned to the human genome (hg19) and methylation levels called using bismark.

阐明正常分化程序的表观遗传调控机制，可为揭示癌症中失调的关键调控状态提供核心信息。本研究采用已建立的非恶性HPr1-AR前列腺上皮细胞模型，该模型在雄激素暴露后可从基底样状态定向转向腔细胞分化轨迹。我们对该细胞转变过程在多个时间点（0小时、1小时、24小时、96小时）的动态转录组进行了系统性分析，并基于人类基因表达特征证实，其表达模式可强烈反映从基底细胞向腔细胞分化的渐进程序。此外，我们通过全基因组亚硫酸氢盐测序（whole genome bisulfite sequencing, WGBS）构建了该分化程序相关的DNA甲基化动态调控模式。针对经10nM二氢睾酮（DHT）处理0、1、24和96小时的HPr1-AR细胞，采用TruSeq甲基化捕获测序开展了分析。将原始测序读段比对至人类基因组（hg19），并使用Bismark软件调用甲基化水平。