Direct identification of A-to-I editing sites with nanopore native RNA sequencing

Journal article

Nguyen, Tram, Heng, Jia, Kaewsapsak, Pornchai, Kok, Eng, Stanojevic, Dominik, Liu, Hao, Cardilla, Angelysia, Praditya, Albert, Yi, Zirong, Lin, Mingwan, Aw, Jong, Ho, Yin, Peh, Kai, Wang, Yuanming, Zhong, Qixing, Heraud-Farlow, Jacki, Xue, Shifeng, Reversade, Bruno, Walkley, Carl Richard, ... Tan, Meng. (2022). Direct identification of A-to-I editing sites with nanopore native RNA sequencing. Nature Methods. 19, pp. 833-844. https://doi.org/10.1038/s41592-022-01513-3
AuthorsNguyen, Tram, Heng, Jia, Kaewsapsak, Pornchai, Kok, Eng, Stanojevic, Dominik, Liu, Hao, Cardilla, Angelysia, Praditya, Albert, Yi, Zirong, Lin, Mingwan, Aw, Jong, Ho, Yin, Peh, Kai, Wang, Yuanming, Zhong, Qixing, Heraud-Farlow, Jacki, Xue, Shifeng, Reversade, Bruno, Walkley, Carl Richard, Ho, Ying, Sikic, Mile, Wan, Yue and Tan, Meng
Abstract

Inosine is a prevalent RNA modification in animals and is formed when an adenosine is deaminated by the ADAR family of enzymes. Traditionally, inosines are identified indirectly as variants from Illumina RNA-sequencing data because they are interpreted as guanosines by cellular machineries. However, this indirect method performs poorly in protein-coding regions where exons are typically short, in non-model organisms with sparsely annotated single-nucleotide polymorphisms, or in disease contexts where unknown DNA mutations are pervasive. Here, we show that Oxford Nanopore direct RNA sequencing can be used to identify inosine-containing sites in native transcriptomes with high accuracy. We trained convolutional neural network models to distinguish inosine from adenosine and guanosine, and to estimate the modification rate at each editing site. Furthermore, we demonstrated their utility on the transcriptomes of human, mouse and Xenopus. Our approach expands the toolkit for studying adenosine-to-inosine editing and can be further extended to investigate other RNA modifications.

KeywordsAdenosine genetics ; Animals; Inosine genetics; Mice; Nanopores; RNA Editing; RNA genetics; RNA metabolism; Sequence Analysis
Year01 Jan 2022
JournalNature Methods
Journal citation19, pp. 833-844
PublisherNature Publishing Group
ISSN1548-7091
Digital Object Identifier (DOI)https://doi.org/10.1038/s41592-022-01513-3
PubMed ID35697834
Web address (URL)https://www.nature.com/articles/s41592-022-01513-3
Open accessPublished as non-open access
Research or scholarlyResearch
Page range833-844
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Output statusPublished
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Print13 Jun 2022
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Deposited06 Jan 2023
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© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Place of publicationUnited Kingdom
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Ho, P. W. M., Goradia, A., Russell, M. R., Chalk, Alistair M., Milley, K. M., Baker, E. K., Danks, J. A., Slavin, John, Walia, Mannu K., Crimeen-Irwin, B., Dickins, R. A., Martin, T. John and Walkley, Carl. (2015). Knockdown of PTHR1 in osteosarcoma cells decreases invasion and growth and increases tumor differentiation in vivo. Oncogene. 34(22), pp. 2922 - 2933. https://doi.org/10.1038/onc.2014.217
RARγ is a negative regulator of osteoclastogenesis
Green, Alanna C., Poulton, Ingrid J., Vrahnas, Christina, Häusler, Karl D., Walkley, Carl, Wu, Joy Y., Martin, T. John, Gillespie, Matthew T., Chandraratna, Roshantha A. S., Quinn, Julian M. W., Sims, Natalie A. and Purton, L. E.. (2015). RARγ is a negative regulator of osteoclastogenesis. The Journal of Steroid Biochemistry and Molecular Biology. 150, pp. 46 - 53. https://doi.org/10.1016/j.jsbmb.2015.03.005
Brief report: The differential roles of mTORC1 and mTORC2 in mesenchymal stem cell differentiation
Martin, Sally K., Fitter, Stephen, Dutta, Ankit K., Matthews, Mary P., Walkley, Carl, Hall, Michael N., Ruegg, Markus A., Gronthos, Stan and Zannettino, Andrew C. W.. (2015). Brief report: The differential roles of mTORC1 and mTORC2 in mesenchymal stem cell differentiation. Stem Cells. 33(4), pp. 1359 - 1365. https://doi.org/10.1002/stem.1931
Ciliary neurotrophic factor has intrinsic and extrinsic roles in regulating B cell differentiation and bone structure
Askmyr, Maria, White, Kirby E., Jovic, Tanja, King, Hannah A., Quach, Julie M., Maluenda, Ana C., Baker, E. K., Smeets, Monique F., Walkley, Carl and Purton, L. E.. (2015). Ciliary neurotrophic factor has intrinsic and extrinsic roles in regulating B cell differentiation and bone structure. Scientific Reports. 5, pp. 1 - 13. https://doi.org/10.1038/srep15529
PTHrP, its receptor, and protein kinase A activation in osteosarcoma
Walkley, Carl, Walia, Mannu K., Ho, P.W.M. and Martin, T. J.. (2014). PTHrP, its receptor, and protein kinase A activation in osteosarcoma. Molecular & Cellular Oncology. 1(4), pp. 1 - 3. https://doi.org/10.4161/23723548.2014.965624
Gene expression profiling to define the cell intrinsic role of the SKI proto-oncogene in hematopoiesis and myeloid neoplsms
Chalk, Alistair M., Liddicoat, Brian J., Walkley, Carl and Singbrant, Sofie. (2014). Gene expression profiling to define the cell intrinsic role of the SKI proto-oncogene in hematopoiesis and myeloid neoplsms. Genomics Data. 2, pp. 189 - 191. https://doi.org/10.1016/j.gdata.2014.06.022
The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease
Singbrant, Sofie, Wall, Meaghan, Moody, Jennifer, Karlsson, Göran, Chalk, Alistair M., Liddicoat, Brian J., Russell, Megan R., Walkley, Carl R. and Karlsson, Stefan. (2014). The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease. Haematologica. 99(4), pp. 647 - 655. https://doi.org/10.3324/haematol.2013.093971
The Rothmund-Thomson syndrome helicase RECQL4 is essential for hematopoiesis
Smeets, Monique F., DeLuca, Elisabetta, Wall, Meaghan, Quach, Julie M., Chalk, Alistair M., Deans, Andrew J., Heierhorst, Jörg, Purton, Louise E., Izon, David J. and Walkley, Carl R.. (2014). The Rothmund-Thomson syndrome helicase RECQL4 is essential for hematopoiesis. Journal of Clinical Investigation. 124(8), pp. 3551 - 3565. https://doi.org/10.1172/JCI75334
Cells of origin in osteosarcoma: Mesenchymal stem cells or osteoblast committed cells?
Mutsaers, Anthony J. and Walkley, Carl R.. (2014). Cells of origin in osteosarcoma: Mesenchymal stem cells or osteoblast committed cells? Bone. 62, pp. 56 - 63. https://doi.org/10.1016/j.bone.2014.02.003
Immune response to rb1-regulated senescence limits radiation-Induced osteosarcoma formation
Kansara, Maya, Leong, Huei San, Lin, Dan Mei, Popkiss, Sophie, Pang, Puiyi, Garsed, Dale W., Walkley, Carl R., Cullinane, Carleen, Ellul, Jason, Haynes, Nicole M., Hicks, Rod, Kuijjer, Marieke L., Cleton-Jansen, Anne-Marie, Hinds, Philip W., Smyth, Mark J. and Thomas, David M.. (2013). Immune response to rb1-regulated senescence limits radiation-Induced osteosarcoma formation. Journal of Clinical Investigation. 123(12), pp. 5351 - 5360. https://doi.org/10.1172/JCI70559
Erythroid-extrinsic regulation of normal erythropoiesis by retinoic acid receptors
Dewamitta, Sita R., Joseph, Chacko, Purton, Louise E. and Walkley, Carl R.. (2013). Erythroid-extrinsic regulation of normal erythropoiesis by retinoic acid receptors. British Journal of Haematology. 164(2), pp. 280 - 285. https://doi.org/10.1111/bjh.12578
Modeling distinct osteosarcoma subtypes in vivo using Cre: Lox and lineage-restricted transgenic shRNA
Mutsaers, Anthony J., Ng, Alvin J. M., Baker, Emma K., Russell, Megan R., Chalk, Alistair M., Wall, Meaghan, Liddicoat, Brian J. J., Ho, Patricia W. M., Slavin, John L., Goradia, Ankita, Martin, T. John, Purton, Louise E., Dickins, Ross A. and Walkley, Carl R.. (2013). Modeling distinct osteosarcoma subtypes in vivo using Cre: Lox and lineage-restricted transgenic shRNA. Bone. 55(1), pp. 166 - 178. https://doi.org/10.1016/j.bone.2013.02.016
Darbepoietin-alfa has comparable erythropoietic stimulatory effects to recombinant erythropoietin whilst preserving the bone marrow microenvironment
Dewamitta, Sita R., Russell, Megan R., Nandurkar, Harshal and Walkley, Carl R.. (2013). Darbepoietin-alfa has comparable erythropoietic stimulatory effects to recombinant erythropoietin whilst preserving the bone marrow microenvironment. Haematologica. 98(5), pp. 686 - 690. https://doi.org/10.3324/haematol.2012.078709
Deciphering hematopoietic stem cells in their niches: A critical appraisal of genetic models, lineage tracing, and imaging strategies
Joseph, Chacko, Quach, Julie M., Walkley, Carl R., Lane, Steven W., Celso, Cristina Lo and Purton, Louise E.. (2013). Deciphering hematopoietic stem cells in their niches: A critical appraisal of genetic models, lineage tracing, and imaging strategies. Cell Stem Cell. 13(5), pp. 520 - 533. https://doi.org/10.1016/j.stem.2013.10.010
The zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim
Jurado, Sabine, Gleeson, Kimberly, O’Donnell, Kristy, Izon, David J., Walkley, Carl R., Strasser, Andreas, Tarlinton, David M. and Heierhorst, Jörg. (2012). The zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim. Journal of Experimental Medicine. 209(9), pp. 1629-1639. https://doi.org/10.1084/jem.20120785
Fak depletion in both hematopoietic and nonhematopoietic niche cells leads to hematopoietic stem cell expansion
Lu, Jiayun, Sun, Yan, Nombela-Arrieta, Cesar, Du, Karrie P., Park, Shin-Young, Chai, Li, Walkley, Carl, Luo, Hongbo R. and Silberstein, Leslie E.. (2012). Fak depletion in both hematopoietic and nonhematopoietic niche cells leads to hematopoietic stem cell expansion. Experimental Hematology. 40(4), pp. 307-317. https://doi.org/10.1016/j.exphem.2011.11.010
Erythropoietin couples erythropoiesis, B-lymphopoiesis, and bone homeostasis within the bone marrow microenvironment
Singbrant, Sofie, Russell, Megan R., Jovic, Tanja, Liddicoat, Brian, Izon, David J., Purton, Louise E., Sims, Natalie A., Martin, T. John, Sankaran, Vijay G. and Walkley, Carl R.. (2011). Erythropoietin couples erythropoiesis, B-lymphopoiesis, and bone homeostasis within the bone marrow microenvironment. Blood. 117(21), pp. 5631-5642. https://doi.org/10.1182/blood-2010-11-320564
Erythropoiesis, anemia and the bone marrow microenvironment
Walkley, Carl R.. (2011). Erythropoiesis, anemia and the bone marrow microenvironment. International Journal of Hematology. 93, pp. 10-13. https://doi.org/10.1007/s12185-010-0759-6
Defining the hematopoietic stem cell niche : The chicken and the egg conundrum
Singbrant, Sofie, Askmyr, Maria, Purton, Louise E. and Walkley, Carl R.. (2011). Defining the hematopoietic stem cell niche : The chicken and the egg conundrum. Journal of Cellular Biochemistry. 112(6), pp. 1486-1490. https://doi.org/10.1002/jcb.23085
Hematopoietic AMPK beta1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity
Galic, Sandra, Fullerton, Morgan, Schertzer, Jonathan, Sikkema, Sarah, Marcinko, Katarina, Walkley, Carl, Izon, David, Honeyman, Jane, Chen, Zhi-Ping, Van Denderen, Bryce, Kemp, Bruce and Steinberg, Gregory. (2011). Hematopoietic AMPK beta1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. Journal of Clinical Investigation. 121(12), pp. 4903 - 4915. https://doi.org/10.1172/JCI58577
Hematopoietic AMPK Beta ß1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity
Galic, Sandra, Fullerton, Morgan D., Schertzer, Jonathan D., Sikkema, Sarah, Marcinko, Katarina, Walkley, Carl R., Izon, David, Honeyman, Jane, Chen, Zhi-Ping, van Denderen, Bryce J., Kemp, Bruce Ernest and Steinberg, Gregory R.. (2011). Hematopoietic AMPK Beta ß1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. Journal of Clinical Investigation. 121(12), pp. 4903 - 4915. https://doi.org/10.1172/JCI58577