Human RNase L tunes gene expression by selectively destabilizing the microRNA-regulated transcriptome

Sneha Rath; Jesse Donovan; Gena Whitney; Alisha Chitrakar; Wei Wang; Alexei Korennykh

doi:10.1073/pnas.1513034112

Human RNase L tunes gene expression by selectively destabilizing the microRNA-regulated transcriptome

Sneha Rath, Jesse Donovan, Gena Whitney, Alisha Chitrakar, Wei Wang, Alexei Korennykh

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

Abstract

Double-stranded RNA (dsRNA) activates the innate immune system of mammalian cells and triggers intracellular RNA decay by the pseudokinase and endoribonuclease RNase L. RNase L protects from pathogens and regulates cell growth and differentiation by destabilizing largely unknown mammalian RNA targets. We developed an approach for transcriptome-wide profiling of RNase L activity in human cells and identified hundreds of direct RNA targets and nontargets. We show that this RNase L-dependent decay selectively affects transcripts regulated by microRNA (miR)-17/miR-29/miR-200 and other miRs that function as suppressors of mammalian cell adhesion and proliferation. RNase L mimics the effects of these miRs and acts as a suppressor of proliferation and adhesion in mammalian cells. Our data suggest that RNase L-dependent decay serves to establish an antiproliferative state via destabilization of the miR-regulated transcriptome.

Original language	English (US)
Pages (from-to)	15916-15921
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	112
Issue number	52
DOIs	https://doi.org/10.1073/pnas.1513034112
State	Published - Dec 29 2015

All Science Journal Classification (ASJC) codes

General

Keywords

Adhesion
DsRNA
MiR-200
MicroRNA
RNase L

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10.1073/pnas.1513034112

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title = "Human RNase L tunes gene expression by selectively destabilizing the microRNA-regulated transcriptome",

abstract = "Double-stranded RNA (dsRNA) activates the innate immune system of mammalian cells and triggers intracellular RNA decay by the pseudokinase and endoribonuclease RNase L. RNase L protects from pathogens and regulates cell growth and differentiation by destabilizing largely unknown mammalian RNA targets. We developed an approach for transcriptome-wide profiling of RNase L activity in human cells and identified hundreds of direct RNA targets and nontargets. We show that this RNase L-dependent decay selectively affects transcripts regulated by microRNA (miR)-17/miR-29/miR-200 and other miRs that function as suppressors of mammalian cell adhesion and proliferation. RNase L mimics the effects of these miRs and acts as a suppressor of proliferation and adhesion in mammalian cells. Our data suggest that RNase L-dependent decay serves to establish an antiproliferative state via destabilization of the miR-regulated transcriptome.",

keywords = "Adhesion, DsRNA, MiR-200, MicroRNA, RNase L",

author = "Sneha Rath and Jesse Donovan and Gena Whitney and Alisha Chitrakar and Wei Wang and Alexei Korennykh",

note = "Funding Information: We thank Prof. Yibin Kang (Princeton University) for providing HeLa and T47D cell lines, Prof. Robert Silverman (Cleveland Clinic) for the gift of WT and RNase L-KO MEFs, and Prof. Lynne Maquat (University of Rochester School of Medicine) for important suggestions. We acknowledge the staff of the Princeton University sequencing core facility for help with RNA-seq and Lance Parsons (Princeton University) for help with GSEA. We thank Prof. Elizabeth Gavis (Princeton University), Prof. Andrei Korostelev (RNA Therapeutics Institute), and members of the Korennykh laboratory for reading the manuscript and providing valuable comments. This study was funded by Princeton University, NIH Grant 5T32GM007388 (to S.R.), NIH Grant 1R01GM110161-01 (to A.K.), Sidney Kimmel Foundation Grant AWD1004002 (to A.K.), and Burroughs Wellcome Foundation Grant 1013579 (to A.K.).",

year = "2015",

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doi = "10.1073/pnas.1513034112",

language = "English (US)",

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T1 - Human RNase L tunes gene expression by selectively destabilizing the microRNA-regulated transcriptome

AU - Rath, Sneha

AU - Donovan, Jesse

AU - Whitney, Gena

AU - Chitrakar, Alisha

AU - Wang, Wei

AU - Korennykh, Alexei

N1 - Funding Information: We thank Prof. Yibin Kang (Princeton University) for providing HeLa and T47D cell lines, Prof. Robert Silverman (Cleveland Clinic) for the gift of WT and RNase L-KO MEFs, and Prof. Lynne Maquat (University of Rochester School of Medicine) for important suggestions. We acknowledge the staff of the Princeton University sequencing core facility for help with RNA-seq and Lance Parsons (Princeton University) for help with GSEA. We thank Prof. Elizabeth Gavis (Princeton University), Prof. Andrei Korostelev (RNA Therapeutics Institute), and members of the Korennykh laboratory for reading the manuscript and providing valuable comments. This study was funded by Princeton University, NIH Grant 5T32GM007388 (to S.R.), NIH Grant 1R01GM110161-01 (to A.K.), Sidney Kimmel Foundation Grant AWD1004002 (to A.K.), and Burroughs Wellcome Foundation Grant 1013579 (to A.K.).

PY - 2015/12/29

Y1 - 2015/12/29

N2 - Double-stranded RNA (dsRNA) activates the innate immune system of mammalian cells and triggers intracellular RNA decay by the pseudokinase and endoribonuclease RNase L. RNase L protects from pathogens and regulates cell growth and differentiation by destabilizing largely unknown mammalian RNA targets. We developed an approach for transcriptome-wide profiling of RNase L activity in human cells and identified hundreds of direct RNA targets and nontargets. We show that this RNase L-dependent decay selectively affects transcripts regulated by microRNA (miR)-17/miR-29/miR-200 and other miRs that function as suppressors of mammalian cell adhesion and proliferation. RNase L mimics the effects of these miRs and acts as a suppressor of proliferation and adhesion in mammalian cells. Our data suggest that RNase L-dependent decay serves to establish an antiproliferative state via destabilization of the miR-regulated transcriptome.

AB - Double-stranded RNA (dsRNA) activates the innate immune system of mammalian cells and triggers intracellular RNA decay by the pseudokinase and endoribonuclease RNase L. RNase L protects from pathogens and regulates cell growth and differentiation by destabilizing largely unknown mammalian RNA targets. We developed an approach for transcriptome-wide profiling of RNase L activity in human cells and identified hundreds of direct RNA targets and nontargets. We show that this RNase L-dependent decay selectively affects transcripts regulated by microRNA (miR)-17/miR-29/miR-200 and other miRs that function as suppressors of mammalian cell adhesion and proliferation. RNase L mimics the effects of these miRs and acts as a suppressor of proliferation and adhesion in mammalian cells. Our data suggest that RNase L-dependent decay serves to establish an antiproliferative state via destabilization of the miR-regulated transcriptome.

KW - Adhesion

KW - DsRNA

KW - MiR-200

KW - MicroRNA

KW - RNase L

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 52

ER -

Human RNase L tunes gene expression by selectively destabilizing the microRNA-regulated transcriptome

Abstract

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