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

doi:10.1016/j.celrep.2022.110740

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 journal › Article › peer-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 language	American English
Article number	110740
Journal	Cell Reports
Volume	39
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2022.110740
State	Published - 26 Apr 2022

Bibliographical note

Funding Information:
This work was funded by the NIH R01 grant ( R01GM124406 ) to S.K.

Publisher Copyright:
© 2022 The Authors

Keywords

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

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10.1016/j.celrep.2022.110740

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

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.",

keywords = "CP: Molecular biology, Drosophila, MBNL, RNA metabolism, circMbl, circRNA, muscleblind, splicing",

author = "Pamudurti, {Nagarjuna Reddy} and Patop, {Ines Lucia} and Aishwarya Krishnamoorthy and Osnat Bartok and Roni Maya and Noam Lerner and Reut Ashwall-Fluss and Konakondla, {Jacob Vinay Vikas} and Tsevi Beatus and Sebastian Kadener",

note = "Funding Information: This work was funded by the NIH R01 grant ( R01GM124406 ) to S.K. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

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doi = "10.1016/j.celrep.2022.110740",

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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

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.

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KW - Drosophila

KW - MBNL

KW - RNA metabolism

KW - circMbl

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KW - splicing

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

Abstract

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