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Genetic Regulation of Human isomiR Biogenesis

Guanglong Jiang1,2, Jill L Reiter2, Chuanpeng Dong3

  • 1Department of BioHealth Informatics, Luddy School of Informatics, Computing, and Engineering, Indiana University, Indianapolis, IN 46202, USA.

Cancers
|September 9, 2023
PubMed

Insights

Genetic variations called single-nucleotide polymorphisms (SNPs) influence microRNA (miRNA) maturation, affecting isomiR composition. Specific SNP-isomiR associations were found, with altered isomiR expression in breast cancer tissues.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression.
  • IsomiRs, sequence variants of mature miRNAs, expand regulatory capabilities by targeting different mRNAs or competing with canonical miRNAs.
  • Understanding the factors influencing isomiR generation is crucial for comprehending the full spectrum of miRNA-mediated gene regulation.

Purpose of the Study:

  • To investigate the association between cis-acting single-nucleotide polymorphisms (SNPs) in precursor miRNA regions and the resulting isomiR composition.
  • To explore the potential impact of these genetic variations on miRNA target specificity and gene regulation.
  • To examine differences in isomiR expression between breast cancer and normal tissues.

Main Methods:

  • Analysis of precursor miRNA sequences to identify cis-acting single-nucleotide polymorphisms (SNPs).
  • Quantification of isomiR composition, focusing on the ratio of specific 5'-isomiR subtypes to total identified isomiRs for mature miRNAs.
  • Statistical association testing to identify significant SNP-isomiR pairs.
  • Comparative analysis of isomiR expression levels in breast cancer tumor samples versus adjacent normal tissues.

Main Results:

  • Identification of 95 significant associations between specific SNPs and isomiR composition.
  • The SNP rs6505162 showed a significant association with both 5'-extension of hsa-miR-423-3p and 5'-trimming of hsa-miR-423-5p.
  • Expression levels of both associated isomiRs (hsa-miR-423-3p and hsa-miR-423-5p variants) were significantly elevated in breast cancer tumors compared to normal tissues.

Conclusions:

  • Cis-acting SNPs in precursor miRNA regions play a significant role in determining isomiR maturation and composition.
  • Genetic variations can influence the landscape of miRNA isoforms, potentially altering post-transcriptional regulatory networks.
  • Aberrant expression of specific isomiRs, influenced by genetic factors, may contribute to the development or progression of diseases like breast cancer.
Keywords:
genetic associationisomiRmicroRNA

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