Department of Bioinformatics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
Funct Integr Genomics. 2023 Aug 5;23(3):266. doi: 10.1007/s10142-023-01191-0.
With 46 microRNAs (miRNAs) embedded tandemly over a distance of ~100 kb, chromosome 19 microRNA cluster (C19MC) is the largest miRNA cluster in the human genome. The C19MC is transcribed from a long noncoding genomic region and is usually expressed simultaneously at a higher level. Hence, we performed an integrative multiomics data analysis to examine C19MC regulation, expression patterns, and their impact on bladder cancer (BCa). We found that 43 members of C19MC were highly expressed in BCa. However, its co-localization with recurrent copy number variation (CNV) gain was not statistically significant to implicate its upregulation. It has been reported that C19MC expression is regulated by a well-established CpG island situated 17.6 kb upstream of the transcription start site, but we found that CpG probes at this island were hypomethylated, which was not statistically significant in the BCa cohort. In addition, the promoter region of C19MC is strongly regulated by a group of seven transcription factors (NR2F6, SREBF1, TBP, GATA3, GABPB1, ETV4, and ZNF444) and five chromatin modifiers (SMC3, KDMA1, EZH2, RAD21, and CHD7). Interestingly, these 12 genes were found to be overexpressed in BCa patients. Further, C19MC targeted 42 tumor suppressor (TS) genes that were downregulated, of which 15 were significantly correlated with patient survival. Our findings suggest that transcription factors and chromatin modifiers at the promoter region may regulate C19MC overexpression. The upregulated C19MC members, transcription regulators, and TS genes can be further exploited as potential diagnostic and prognostic indicators as well as for therapeutic management of BCa.
19 号染色体微小 RNA 簇（C19MC）是人类基因组中最大的微小 RNA 簇，其包含 46 个微小 RNA（miRNA），串联排列在约 100kb 的距离上。C19MC 由一个长的非编码基因组区域转录而来，通常以更高的水平同时表达。因此，我们进行了综合多组学数据分析，以研究 C19MC 的调控、表达模式及其对膀胱癌（BCa）的影响。我们发现 C19MC 的 43 个成员在 BCa 中高度表达。然而，其与反复出现的拷贝数变异（CNV）增益的共定位并不具有统计学意义，不能说明其上调。据报道，C19MC 的表达受位于转录起始位点上游 17.6kb 的一个成熟 CpG 岛调控，但我们发现该岛上的 CpG 探针呈低甲基化状态，在 BCa 队列中无统计学意义。此外，C19MC 的启动子区域受一组七个转录因子（NR2F6、SREBF1、TBP、GATA3、GABPB1、ETV4 和 ZNF444）和五个染色质修饰物（SMC3、KDMA1、EZH2、RAD21 和 CHD7）的强烈调控。有趣的是，这些 12 个基因在 BCa 患者中被发现过度表达。进一步的，C19MC 靶向了 42 个肿瘤抑制（TS）基因，这些基因被下调，其中 15 个与患者生存显著相关。我们的研究结果表明，启动子区域的转录因子和染色质修饰物可能调控 C19MC 的过表达。上调的 C19MC 成员、转录调控因子和 TS 基因可进一步作为潜在的诊断和预后标志物，以及用于 BCa 的治疗管理。
