Integrated multiomics analysis of chromosome 19 miRNA cluster in bladder cancer

Abstract

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.

Elucidation of how the Mir-23-27-24 cluster regulates development and aging

“…miRNA clusters are defined as those that overlap within a primary transcript, are located in adjacent genome loci and are transcribed in the same direction 6 . Generally, miRNA clusters comprise two to three miRNAs, yet large miRNA clusters also occur, such as the chromosome 19 miRNA cluster (C19MC), which is the largest in the human genome, comprising 46 miRNAs that span ~100 kilobases 7 . Since individual miRNAs have various target genes, a miRNA cluster ultimately evolves complex regulatory activity, thereby influencing a diverse array of biological processes.…”

Editorial Comment to CHARGE syndrome with both primary and secondary hypogonadism

“…reported a decrease in the expression of CHD7 in testicular tissue in boys with high infertility risk, which was defined by decreased spermatogonia. 2 Additionally, overexpression of CHD7 in bladder cancer 3 or mutation in the CHD7 gene in colorectal cancer 4 has been reported, which suggests a hypothetical role of CHD7 on carcinogenesis. Thus, the direct effect of dysfunction of CHD7 in the testicular tissue should be considered.…”