circMbl Functions in cis and in trans to Regulate Gene Expression With Impacts on Physiology

Abstract

Muscleblind (mbl) is an essential muscle and neuronal splicing regulator and the causative agent of myotonic dystrophy. Mbl hosts an abundant circular RNA, 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. First, we generated fly lines to specifically modulate the levels of all mbl RNA isoforms. We found that the two major mbl protein isoforms, MBL-O/P and MBL-C, buffer their own levels by producing different circRNA isoforms in the eye and fly brain respectively. Moreover, we show that circMbl has unique functions in trans, as knockdown of circMbl resulted in specific morphological and physiological phenotypes. Moreover, 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.

Keywords: circRNA, muscleblind, MBNL, Drosophila, RNA metabolism, circMbl, myotonic dystrophy