Integrated multiomics analysis of chromosome 19 miRNA cluster in bladder cancer

With 46 microRNAs (miRNAs) embedded tandemly over a distance of similar to 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.

Automated summary

Chromosome 19 microRNA cluster (C19MC) is the largest miRNA cluster in humans, consisting of 46 miRNAs embedded tandemly. In this study, we examined the regulation, expression patterns, and impact of C19MC on bladder cancer (BCa) using multiomics data analysis. We found that 43 C19MC members were highly expressed in BCa, but their co-localization with copy number variation (CNV) gain was not statistically significant. The CpG probes at the well-established CpG island upstream of the transcription start site were hypomethylated, and the promoter region of C19MC was regulated by a group of transcription factors and chromatin modifiers. Furthermore, C19MC targeted multiple tumor suppressor genes that were downregulated and correlated with patient survival. These findings suggest the potential of using C19MC and its regulators as diagnostic, prognostic, and therapeutic indicators for BCa.