TY - JOUR
T1 - circMbl functions in cis and in trans to regulate gene expression and physiology in a tissue-specific fashion
AU - Pamudurti, Nagarjuna Reddy
AU - Patop, Ines Lucia
AU - Krishnamoorthy, Aishwarya
AU - Bartok, Osnat
AU - Maya, Roni
AU - Lerner, Noam
AU - Ashwall-Fluss, Reut
AU - Konakondla, Jacob Vinay Vikas
AU - Beatus, Tsevi
AU - Kadener, Sebastian
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2022/4/26
Y1 - 2022/4/26
N2 - 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.
AB - 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.
KW - CP: Molecular biology
KW - Drosophila
KW - MBNL
KW - RNA metabolism
KW - circMbl
KW - circRNA
KW - muscleblind
KW - splicing
UR - http://www.scopus.com/inward/record.url?scp=85128982001&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2022.110740
DO - 10.1016/j.celrep.2022.110740
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C2 - 35476987
AN - SCOPUS:85128982001
SN - 2211-1247
VL - 39
JO - Cell Reports
JF - Cell Reports
IS - 4
M1 - 110740
ER -