PDF(Pubmed)
Abstract：
BACKGROUND: Prostate adenocarcinoma (PRAD) is the second leading cause of cancer-related deaths in men. High variability in DNA methylation and a high rate of large genomic rearrangements are often observed in PRAD.
RESULTS: To investigate the reasons for such high variance, we integrated DNA methylation, RNA-seq, and copy number alterations datasets from The Cancer Genome Atlas (TCGA), focusing on PRAD, and employed weighted gene co-expression network analysis (WGCNA). Our results show that only 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 discovered that TP63 regulates the level of enhancer methylation in prostate basal epithelial cells. TRIM29 forms a complex with TP63 and together regulates the expression of genes specific to the prostate basal epithelium. In addition, TRIM29 binds DNA repair proteins and prevents the formation of the TMPRSS2:ERG gene fusion typically observed in PRAD.
CONCLUSIONS: Our study demonstrates that TRIM29 and TP63 are important regulators in maintaining the identity of the basal epithelium under physiological conditions. Furthermore, we uncover the role of TRIM29 in PRAD development.
RESULTS: To investigate the reasons for such high variance, we integrated DNA methylation, RNA-seq, and copy number alterations datasets from The Cancer Genome Atlas (TCGA), focusing on PRAD, and employed weighted gene co-expression network analysis (WGCNA). Our results show that only 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 discovered that TP63 regulates the level of enhancer methylation in prostate basal epithelial cells. TRIM29 forms a complex with TP63 and together regulates the expression of genes specific to the prostate basal epithelium. In addition, TRIM29 binds DNA repair proteins and prevents the formation of the TMPRSS2:ERG gene fusion typically observed in PRAD.
CONCLUSIONS: Our study demonstrates that TRIM29 and TP63 are important regulators in maintaining the identity of the basal epithelium under physiological conditions. Furthermore, we uncover the role of TRIM29 in PRAD development.
摘要：
背景：前列腺癌（PRAD）是男性癌症相关死亡的第二大原因。在PRAD中经常观察到DNA甲基化的高变异性和大基因组重排的高比率。
结果：为了调查如此高差异的原因，我们整合了DNA甲基化，RNA-seq,和来自癌症基因组图谱(TCGA)的拷贝数改变数据集，专注于PRAD，并采用加权基因共表达网络分析(WGCNA)。我们的结果表明，共表达基因的单个簇与基因组和表观基因组的不稳定性有关。在这个集群中，TP63和TRIM29是关键的转录调节因子，在PRAD中下调。我们发现TP63调节前列腺基底上皮细胞中增强子甲基化的水平。TRIM29与TP63形成复合物，并共同调节前列腺基底上皮特异性基因的表达。此外,TRIM29结合DNA修复蛋白并防止通常在PRAD中观察到的TMPRSS2:ERG基因融合体的形成。
结论：我们的研究表明，在生理条件下，TRIM29和TP63是维持基底上皮身份的重要调节因子。此外，我们揭示了TRIM29在PRAD开发中的作用。
结果：为了调查如此高差异的原因，我们整合了DNA甲基化，RNA-seq,和来自癌症基因组图谱(TCGA)的拷贝数改变数据集，专注于PRAD，并采用加权基因共表达网络分析(WGCNA)。我们的结果表明，共表达基因的单个簇与基因组和表观基因组的不稳定性有关。在这个集群中，TP63和TRIM29是关键的转录调节因子，在PRAD中下调。我们发现TP63调节前列腺基底上皮细胞中增强子甲基化的水平。TRIM29与TP63形成复合物，并共同调节前列腺基底上皮特异性基因的表达。此外,TRIM29结合DNA修复蛋白并防止通常在PRAD中观察到的TMPRSS2:ERG基因融合体的形成。
结论：我们的研究表明，在生理条件下，TRIM29和TP63是维持基底上皮身份的重要调节因子。此外，我们揭示了TRIM29在PRAD开发中的作用。
