Genetic Regulation of Human isomiR Biogenesis

SIMPLE SUMMARY: This study investigated the cis-regulation of isomiR biogenesis in human lymphoblastoid cell lines. A total of 95 SNP–isomiR pairs demonstrated significant associations between SNPs and 5′-isomiRs, including base substitutions, trimmings, extensions, and additions. Notably, the study identified an association between rs6505162 and the 5′-extension of hsa-miR-423-3p, as well as the 5′-trimming of hsa-miR-423-5p. Additionally, the correlation of isomiR expression with breast cancer status in the TCGA dataset provided valuable insights into the genetic association with breast cancer tumorigenesis. The study also highlighted that canonical miRNAs may not be the most abundant isomiRs in human lymphoblastoid cell lines, emphasizing the role of isomiRs in biological processes. Furthermore, the presence of the allele-specific expression of miRNAs suggests the involvement of genetic variants in miRNA regulation. ABSTRACT: MicroRNAs play a critical role in regulating gene expression post-transcriptionally. Variations in mature microRNA sequences, known as isomiRs, arise from imprecise cleavage and nucleotide substitution or addition. These isomiRs can target different mRNAs or compete with their canonical counterparts, thereby expanding the scope of miRNA post-transcriptional regulation. Our study investigated the relationship between cis-acting single-nucleotide polymorphisms (SNPs) in precursor miRNA regions and isomiR composition, represented by the ratio of a specific 5′-isomiR subtype to all isomiRs identified for a particular mature miRNA. Significant associations between 95 SNP–isomiR pairs were identified. Of note, rs6505162 was significantly associated with both the 5′-extension of hsa-miR-423-3p and the 5′-trimming of hsa-miR-423-5p. Comparison of breast cancer and normal samples revealed that the expression of both isomiRs was significantly higher in tumors than in normal tissues. This study sheds light on the genetic regulation of isomiR maturation and advances our understanding of post-transcriptional regulation by microRNAs.