Login to Access Video or Poster Abstract: MP82-08
Sources of Funding: SNSF Grant 320030_156161/1, Velux Foundation Grant 895 _x000D_ _x000D_

Introduction

MicroRNAs regulate diverse biological processes. Previously we identified miRNA-regulated pathways in bladder outlet obstruction (BOO)-induced bladder dysfunction. MiRNAs in a cluster reside in genomic proximity (<10 kb) and their expression might be mediated by common transcription factors. Here we probed functional associations of BOO phenotype-specific miRNAs and identified several co-expressed miRNA sub-networks.

Methods

MiRNA sequences and genomic coordinates were extracted from miRBase version 21. Large scale chromosomal mapping of human miRNA structural clusters was done using MIReStruC-1.0 package. Next-generation sequencing datasets of patients&[prime] biopsies with urodynamically established BOO with and without detrusor overactivity (DO and BO groups, respectively) or with detrusor underactivity (UA group) were used to perform miRNA-mRNA integrated analysis and target pairing. Sequences were aligned with MAFFT version 7 and Clustal X 2.1 and manually refined with RALEE-RNA version 0.8.

Results

In DO group hsa-miR-376c-3p/hsa-miR-409-3p cluster was identified on chromosome 14. In BO group hsa-miR-889-3p/hsa-miR-410-3p/hsa-miR-409-3p cluster was detected on chromosome 14. Three miRNA clusters were detected in UA group: hsa-miR-25-3p/hsa-miR-106b-3p cluster on chromosome 7, and 2 clusters on chromosome 1: hsa-miR-199a-3p/hsa-miR-3120-3p cluster and hsa-miR-429/hsa-miR-200b-3p cluster belonging to miR-200bc/429/548a family. Integrated miRNA-mRNA expression profiling revealed no significant target overlap, and 90% of targets of up-regulated miRNA clusters were also up-regulated. No major contribution of the miRNA clusters to the biological functions of miRNA-regulated pathways was detected in DO and BO groups. In UA group 2 down-regulated hsa-miR-199a-3p/hsa-miR-3120-3p and hsa-miR-429/hsa-miR-200b-3p miRNA clusters were necessary and sufficient to determine the functions of all miRNA-regulated pathways and their targets constituted the majority of miRNA-regulated pathway elements.

Conclusions

Multiple co-expressed miRNAs may cooperatively influence biological processes and the acontractile urodynamic phenotype in the underactive bladder. Elucidating the down-regulation mechanisms of these miRNA clusters may help determine the &[raquo]point of no return&[laquo] for the loss of bladder function during BOO.

Funding

SNSF Grant 320030_156161/1, Velux Foundation Grant 895 _x000D_ _x000D_