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MBNL splicing factors regulate the microtranscriptome of skeletal muscles

Agnieszka Piasecka1, Michał W Szcześniak2, Michał Sekrecki1

  • 1Laboratory of Gene Therapy, Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Uniwersytetu Poznanskiego 6, 61-614 Poznań, Poland.

Nucleic Acids Research
|September 11, 2024
PubMed

Insights

Muscleblind like splicing regulators (MBNLs) control RNA processing. In myotonic dystrophy type 1 (DM1), MBNL sequestration disrupts microRNA (miRNA) regulation in skeletal muscles, impacting disease progression.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Genetics

Background:

  • Muscleblind like splicing regulators (MBNLs) are crucial for RNA processing, including alternative splicing and mRNA localization.
  • In myotonic dystrophy type 1 (DM1), MBNLs are sequestered by toxic CUG repeat RNA, disrupting normal cellular functions and contributing to disease pathology.
  • MicroRNAs (miRNAs) play vital roles in gene regulation and are implicated in various diseases, including muscular dystrophies.

Purpose of the Study:

  • To investigate the role of MBNLs in regulating microtranscriptome dynamics during postnatal skeletal muscle development.
  • To elucidate the mechanisms by which MBNL deficiency leads to miRNA misregulation in DM1.
  • To identify specific miRNAs affected by MBNL insufficiency and their potential contribution to DM1 pathogenesis.

Main Methods:

  • Analysis of miRNA expression profiles in Mbnl1-knockout mice and DM1 patient samples.
  • Investigation of MBNL protein levels and their correlation with miRNA expression during muscle development.
  • Examination of pri-miRNA levels and alternative splicing events in miRNA primary transcripts.
  • Functional studies on specific miRNA clusters regulated by MBNLs.

Main Results:

  • MBNLs are significant regulators of miRNA expression during postnatal skeletal muscle development.
  • MBNL insufficiency leads to altered miRNA levels, with an adult-to-newborn shift observed in Mbnl1-knockout mice.
  • MBNL deficiency affects miRNA biogenesis through modulation of pri-miRNA levels and alternative splicing of miRNA precursors.
  • Specific miRNAs, including those from the miR-23b/27b/24-1 cluster, are sensitive to MBNL levels.

Conclusions:

  • MBNL sequestration in DM1 contributes to altered miRNA activity, impacting skeletal muscle function.
  • MBNLs act as key regulators of the microtranscriptome in skeletal muscle, particularly during postnatal development.
  • Understanding MBNL-mediated miRNA regulation provides new insights into DM1 pathogenesis and potential therapeutic strategies.

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