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Alternative splicing regulates biogenesis of miRNAs located across exon-intron junctions

Ze'ev Melamed1, Asaf Levy, Reut Ashwal-Fluss

  • 1Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.

Molecular Cell
|June 11, 2013
PubMed

Insights

RNA splicing negatively regulates microRNA (miRNA) processing when precursor miRNAs (pre-miRNAs) overlap exon-intron junctions. Alternative splicing controls this process, impacting miRNA targets and neuronal cell death pathways.

Area of Science:

  • Molecular Biology
  • Genetics
  • RNA Biology

Background:

  • MicroRNA (miRNA) biogenesis involves processing precursor miRNAs (pre-miRNAs) from primary transcripts.
  • Many pre-miRNAs are derived from introns, allowing co-generation of mature miRNAs and spliced RNAs from a single transcription unit.
  • The interplay between RNA splicing and miRNA processing is not fully understood.

Purpose of the Study:

  • To identify and characterize mechanisms where RNA splicing regulates pre-miRNA processing.
  • To investigate the role of alternative splicing in controlling miRNA maturation.
  • To explore the functional consequences of splice-site-overlapping pre-miRNA regulation.

Main Methods:

  • Computational analysis to identify pre-miRNAs overlapping exon-intron junctions.
  • Experimental validation of identified pre-miRNAs and their processing.
  • Investigation of competitive interactions between the Microprocessor complex and splicing machinery.

Main Results:

  • A novel mechanism was identified where RNA splicing negatively regulates the processing of pre-miRNAs overlapping exon-intron junctions.
  • Dozens of such pre-miRNAs were computationally identified and experimentally validated.
  • Tissue-specific alternative splicing was shown to regulate the maturation of miR-412, affecting a protein network involved in neuronal cell death.

Conclusions:

  • Alternative splicing plays a biological role in regulating miRNA biogenesis, specifically for splice-site-overlapping pre-miRNAs.
  • This regulatory mode differs from controls affecting intronic or exonic pre-miRNAs.
  • The findings reveal a new layer of gene expression control impacting neuronal function.

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