circMbl functions in cis and in trans to regulate gene expression and physiology in a tissue-specific fashion

Nagarjuna Reddy Pamudurti, Ines Lucia Patop, Aishwarya Krishnamoorthy, Osnat Bartok, Roni Maya, Noam Lerner, Reut Ashwall-Fluss, Jacob Vinay Vikas Konakondla, Tsevi Beatus, Sebastian Kadener*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Muscleblind (mbl) is an essential muscle and neuronal splicing regulator. Mbl hosts multiple circular RNAs (circRNAs), including circMbl, which is conserved from flies to humans. Here, we show that mbl-derived circRNAs are key regulators of MBL by cis- and trans-acting mechanisms. By generating fly lines to specifically modulate the levels of all mbl RNA isoforms, including circMbl, we demonstrate that the two major mbl protein isoforms, MBL-O/P and MBL-C, buffer their own levels by producing different types of circRNA isoforms in the eye and fly brain, respectively. Moreover, we show that circMbl has unique functions in trans, as knockdown of circMbl results in specific morphological and physiological phenotypes. In addition, depletion of MBL-C or circMbl results in opposite behavioral phenotypes, showing that they also regulate each other in trans. Together, our results illuminate key aspects of mbl regulation and uncover cis and trans functions of circMbl in vivo.

Original languageAmerican English
Article number110740
JournalCell Reports
Volume39
Issue number4
DOIs
StatePublished - 26 Apr 2022

Bibliographical note

Publisher Copyright:
© 2022 The Authors

Keywords

  • CP: Molecular biology
  • Drosophila
  • MBNL
  • RNA metabolism
  • circMbl
  • circRNA
  • muscleblind
  • splicing

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