High-purity circular RNA isolation method (RPAD) reveals vast collection of intronic circRNAs

High-throughput RNA sequencing methods coupled with specialized bioinformatic analyses have recently uncovered tens of thousands of unique circular (circ)RNAs, but their complete sequences, genes of origin and functions are largely unknown. Given that circRNAs lack free ends and are thus relatively...

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Published in:	Nucleic acids research Vol. 45; no. 12; p. e116
Main Authors:	Panda, Amaresh C., De, Supriyo, Grammatikakis, Ioannis, Munk, Rachel, Yang, Xiaoling, Piao, Yulan, Dudekula, Dawood B., Abdelmohsen, Kotb, Gorospe, Myriam
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 07.07.2017
Subjects:	Animals Base Sequence Cell Line Computational Biology Exons Exoribonucleases - chemistry HeLa Cells High-Throughput Nucleotide Sequencing Humans Introns Methods Online Mice Molecular Sequence Annotation Myoblasts - cytology Myoblasts - metabolism Poly A - genetics Poly A - metabolism Polyadenylation RNA - genetics RNA - isolation & purification RNA - metabolism RNA Cleavage RNA, Messenger - chemistry RNA, Messenger - genetics RNA, Messenger - metabolism
ISSN:	0305-1048, 1362-4962, 1362-4962
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Abstract	High-throughput RNA sequencing methods coupled with specialized bioinformatic analyses have recently uncovered tens of thousands of unique circular (circ)RNAs, but their complete sequences, genes of origin and functions are largely unknown. Given that circRNAs lack free ends and are thus relatively stable, their association with microRNAs (miRNAs) and RNA-binding proteins (RBPs) can influence gene expression programs. While exoribonuclease treatment is widely used to degrade linear RNAs and enrich circRNAs in RNA samples, it does not efficiently eliminate all linear RNAs. Here, we describe a novel method for the isolation of highly pure circRNA populations involving RNase R treatment followed by Polyadenylation and poly(A)+ RNA Depletion (RPAD), which removes linear RNA to near completion. High-throughput sequencing of RNA prepared using RPAD from human cervical carcinoma HeLa cells and mouse C2C12 myoblasts led to two surprising discoveries: (i) many exonic circRNA (EcircRNA) isoforms share an identical backsplice sequence but have different body sizes and sequences, and (ii) thousands of novel intronic circular RNAs (IcircRNAs) are expressed in cells. In sum, isolating high-purity circRNAs using the RPAD method can enable quantitative and qualitative analyses of circRNA types and sequence composition, paving the way for the elucidation of circRNA functions.
AbstractList	High-throughput RNA sequencing methods coupled with specialized bioinformatic analyses have recently uncovered tens of thousands of unique circular (circ)RNAs, but their complete sequences, genes of origin and functions are largely unknown. Given that circRNAs lack free ends and are thus relatively stable, their association with microRNAs (miRNAs) and RNA-binding proteins (RBPs) can influence gene expression programs. While exoribonuclease treatment is widely used to degrade linear RNAs and enrich circRNAs in RNA samples, it does not efficiently eliminate all linear RNAs. Here, we describe a novel method for the isolation of highly pure circRNA populations involving RNase R treatment followed by Polyadenylation and poly(A)+ RNA Depletion (RPAD), which removes linear RNA to near completion. High-throughput sequencing of RNA prepared using RPAD from human cervical carcinoma HeLa cells and mouse C2C12 myoblasts led to two surprising discoveries: (i) many exonic circRNA (EcircRNA) isoforms share an identical backsplice sequence but have different body sizes and sequences, and (ii) thousands of novel intronic circular RNAs (IcircRNAs) are expressed in cells. In sum, isolating high-purity circRNAs using the RPAD method can enable quantitative and qualitative analyses of circRNA types and sequence composition, paving the way for the elucidation of circRNA functions. High-throughput RNA sequencing methods coupled with specialized bioinformatic analyses have recently uncovered tens of thousands of unique circular (circ)RNAs, but their complete sequences, genes of origin and functions are largely unknown. Given that circRNAs lack free ends and are thus relatively stable, their association with microRNAs (miRNAs) and RNA-binding proteins (RBPs) can influence gene expression programs. While exoribonuclease treatment is widely used to degrade linear RNAs and enrich circRNAs in RNA samples, it does not efficiently eliminate all linear RNAs. Here, we describe a novel method for the isolation of highly pure circRNA populations involving RNase R treatment followed by Polyadenylation and poly(A)+ RNA Depletion (RPAD), which removes linear RNA to near completion. High-throughput sequencing of RNA prepared using RPAD from human cervical carcinoma HeLa cells and mouse C2C12 myoblasts led to two surprising discoveries: (i) many exonic circRNA (EcircRNA) isoforms share an identical backsplice sequence but have different body sizes and sequences, and (ii) thousands of novel intronic circular RNAs (IcircRNAs) are expressed in cells. In sum, isolating high-purity circRNAs using the RPAD method can enable quantitative and qualitative analyses of circRNA types and sequence composition, paving the way for the elucidation of circRNA functions.High-throughput RNA sequencing methods coupled with specialized bioinformatic analyses have recently uncovered tens of thousands of unique circular (circ)RNAs, but their complete sequences, genes of origin and functions are largely unknown. Given that circRNAs lack free ends and are thus relatively stable, their association with microRNAs (miRNAs) and RNA-binding proteins (RBPs) can influence gene expression programs. While exoribonuclease treatment is widely used to degrade linear RNAs and enrich circRNAs in RNA samples, it does not efficiently eliminate all linear RNAs. Here, we describe a novel method for the isolation of highly pure circRNA populations involving RNase R treatment followed by Polyadenylation and poly(A)+ RNA Depletion (RPAD), which removes linear RNA to near completion. High-throughput sequencing of RNA prepared using RPAD from human cervical carcinoma HeLa cells and mouse C2C12 myoblasts led to two surprising discoveries: (i) many exonic circRNA (EcircRNA) isoforms share an identical backsplice sequence but have different body sizes and sequences, and (ii) thousands of novel intronic circular RNAs (IcircRNAs) are expressed in cells. In sum, isolating high-purity circRNAs using the RPAD method can enable quantitative and qualitative analyses of circRNA types and sequence composition, paving the way for the elucidation of circRNA functions.
Author	Piao, Yulan Abdelmohsen, Kotb Panda, Amaresh C. Gorospe, Myriam Grammatikakis, Ioannis Dudekula, Dawood B. De, Supriyo Yang, Xiaoling Munk, Rachel
AuthorAffiliation	Laboratory of Genetics and Genomics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
AuthorAffiliation_xml	– name: Laboratory of Genetics and Genomics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
Author_xml	– sequence: 1 givenname: Amaresh C. surname: Panda fullname: Panda, Amaresh C. organization: Laboratory of Genetics and Genomics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA – sequence: 2 givenname: Supriyo surname: De fullname: De, Supriyo organization: Laboratory of Genetics and Genomics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA – sequence: 3 givenname: Ioannis surname: Grammatikakis fullname: Grammatikakis, Ioannis organization: Laboratory of Genetics and Genomics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA – sequence: 4 givenname: Rachel surname: Munk fullname: Munk, Rachel organization: Laboratory of Genetics and Genomics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA – sequence: 5 givenname: Xiaoling surname: Yang fullname: Yang, Xiaoling organization: Laboratory of Genetics and Genomics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA – sequence: 6 givenname: Yulan surname: Piao fullname: Piao, Yulan organization: Laboratory of Genetics and Genomics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA – sequence: 7 givenname: Dawood B. surname: Dudekula fullname: Dudekula, Dawood B. organization: Laboratory of Genetics and Genomics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA – sequence: 8 givenname: Kotb surname: Abdelmohsen fullname: Abdelmohsen, Kotb organization: Laboratory of Genetics and Genomics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA – sequence: 9 givenname: Myriam surname: Gorospe fullname: Gorospe, Myriam organization: Laboratory of Genetics and Genomics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
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Snippet	High-throughput RNA sequencing methods coupled with specialized bioinformatic analyses have recently uncovered tens of thousands of unique circular (circ)RNAs,...
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SubjectTerms	Animals Base Sequence Cell Line Computational Biology Exons Exoribonucleases - chemistry HeLa Cells High-Throughput Nucleotide Sequencing Humans Introns Methods Online Mice Molecular Sequence Annotation Myoblasts - cytology Myoblasts - metabolism Poly A - genetics Poly A - metabolism Polyadenylation RNA - genetics RNA - isolation & purification RNA - metabolism RNA Cleavage RNA, Messenger - chemistry RNA, Messenger - genetics RNA, Messenger - metabolism
Title	High-purity circular RNA isolation method (RPAD) reveals vast collection of intronic circRNAs
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