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Ibrahim NA, Shalaby IM, Ghobashy MA, Taeleb AA, Elkhawass EA. Filling the void: Morphological and molecular phylogenetic analyses of helminths assemblage from the Egyptian egret Bubulcus ibis. Parasitol Int 2025; 104:102972. [PMID: 39307346 DOI: 10.1016/j.parint.2024.102972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 09/09/2024] [Accepted: 09/17/2024] [Indexed: 09/26/2024]
Abstract
The cattle egret (B. ibis) as a common wader birds in Egypt, they act a sole reservoir for many parasites and play a vital role in their life cycle and their distribution in their environment. The study was conducted from September 2020 to August 2021. A total of 180 B. ibis were collected from Al Qantara Gharb, Ismailia province, Egypt. Parasite species identification infecting cattle egret included morphological and morphometric characteristics based on light and scanning microscopy. Additionally, utilizing the partial small subunit ribosomal RNA (18S rRNA, ITS2 and ITS1) gene sequence, maximum parsimony was used to infer the phylogeny of the recovered species. The morphological and molecular studies revealed three helminths. Only one nematode (Desportesius invaginatus, linstow,1901) and two trematodes (Patagifer bilobus, Dietz,1909 and Apharyngostrigea cornu, Zeder,1800) have been identified. The cattle egret (B. ibis) are protagonists in the life cycle of many parasites. The study is considered the first in Egypt to fill the gap of phylogenetic analysis of three helminths; two of them (A. cornu and P. bilobus) were the first to be molecular phylogenetically analyzed in Egypt. The molecular data provided set the conspecific relation of the three identified helminths species with other related helminths. The new identified sequences will help in founding the basis for forthcoming identifications of other helminths species from cattle egret in Egypt and prospective view to possible parasitic assemblage affecting egret population and other animal populations in their environment.
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Affiliation(s)
- Nada A Ibrahim
- Zoology Department, Faculty of Science, Suez Canal University, Ismailia, Egypt
| | - Ismail M Shalaby
- Zoology Department, Faculty of Science, Suez Canal University, Ismailia, Egypt
| | - Mahi A Ghobashy
- Zoology Department, Faculty of Science, Suez Canal University, Ismailia, Egypt
| | - Azza A Taeleb
- Zoology Department, Faculty of Science, Zagazig University, Zagazig, Egypt
| | - Elham A Elkhawass
- Zoology Department, Faculty of Science, Suez Canal University, Ismailia, Egypt.
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2
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Wu Y, Xie X, Zhu J, Guan L, Li M. Overview and Prospects of DNA Sequence Visualization. Int J Mol Sci 2025; 26:477. [PMID: 39859192 PMCID: PMC11764684 DOI: 10.3390/ijms26020477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 12/30/2024] [Accepted: 01/04/2025] [Indexed: 01/27/2025] Open
Abstract
Due to advances in big data technology, deep learning, and knowledge engineering, biological sequence visualization has been extensively explored. In the post-genome era, biological sequence visualization enables the visual representation of both structured and unstructured biological sequence data. However, a universal visualization method for all types of sequences has not been reported. Biological sequence data are rapidly expanding exponentially and the acquisition, extraction, fusion, and inference of knowledge from biological sequences are critical supporting technologies for visualization research. These areas are important and require in-depth exploration. This paper elaborates on a comprehensive overview of visualization methods for DNA sequences from four different perspectives-two-dimensional, three-dimensional, four-dimensional, and dynamic visualization approaches-and discusses the strengths and limitations of each method in detail. Furthermore, this paper proposes two potential future research directions for biological sequence visualization in response to the challenges of inefficient graphical feature extraction and knowledge association network generation in existing methods. The first direction is the construction of knowledge graphs for biological sequence big data, and the second direction is the cross-modal visualization of biological sequences using machine learning methods. This review is anticipated to provide valuable insights and contributions to computational biology, bioinformatics, genomic computing, genetic breeding, evolutionary analysis, and other related disciplines in the fields of biology, medicine, chemistry, statistics, and computing. It has an important reference value in biological sequence recommendation systems and knowledge question answering systems.
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Affiliation(s)
| | | | | | | | - Mengshan Li
- School of Mathematics and Computer Science, Gannan Normal University, Ganzhou 341000, China; (Y.W.); (X.X.); (J.Z.); (L.G.)
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3
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Stolc V, Karhanek M, Freund F, Griko Y, Loftus DJ, Ohayon MM. Metabolic stress in space: ROS-induced mutations in mice hint at a new path to cancer. Redox Biol 2024; 78:103398. [PMID: 39586121 PMCID: PMC11625351 DOI: 10.1016/j.redox.2024.103398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 10/14/2024] [Indexed: 11/27/2024] Open
Abstract
Long-duration spaceflight beyond Earth's magnetosphere poses serious health risks, including muscle atrophy, bone loss, liver and kidney damage, and the Spaceflight-Associated Neuro-ocular Syndrome (SANS). RNA-seq of mice aboard the International Space Station (ISS) for 37 days revealed extraordinary hypermutation in tissue-specific genes, with guanine base conversion predominating, potentially contributing to spaceflight-associated health risks. Our results suggest that the genome-wide accelerated mutation that we measured, seemingly independent of radiation dose, was induced by oxidative damage from higher atmospheric carbon dioxide (CO2) levels and increased reactive oxygen species (ROS) on the ISS. This accelerated mutation, faster via RNA transcription than replication and more numerous than by radiation alone, unveils novel hotspots in the mammalian proteome. Notably, these hotspots correlate with commonly mutated genes across various human cancers, highlighting the ISS as a crucial platform for studying accelerated mutation, genome instability, and the induction of disease-causing mutations in model organisms. Our results suggest that metabolic processes can contribute to somatic mutation, and thus may play a role in the development of cancer. A metabolic link to genetic instability potentially has far-reaching implications for various diseases, with implications for human health on Earth and in space.
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Affiliation(s)
- Viktor Stolc
- NASA Ames Research Center, Moffett Field, CA, 94035, USA.
| | - Miloslav Karhanek
- Biomedical Research Center, Slovak Academy of Sciences, 845 05, Bratislava, Slovakia
| | | | - Yuri Griko
- NASA Ames Research Center, Moffett Field, CA, 94035, USA
| | - David J Loftus
- NASA Ames Research Center, Moffett Field, CA, 94035, USA
| | - Maurice M Ohayon
- Stanford University, School of Medicine, Stanford, CA, 94305, USA
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Li Z, Luo L, Ju X, Huang S, Lei L, Yu Y, Liu J, Zhang P, Chi T, Ma P, Huang C, Huang X, Ding Q, Zhang Y. Viral N protein hijacks deaminase-containing RNA granules to enhance SARS-CoV-2 mutagenesis. EMBO J 2024; 43:6444-6468. [PMID: 39567830 PMCID: PMC11649915 DOI: 10.1038/s44318-024-00314-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 10/28/2024] [Accepted: 11/06/2024] [Indexed: 11/22/2024] Open
Abstract
Host cell-encoded deaminases act as antiviral restriction factors to impair viral replication and production through introducing mutations in the viral genome. We sought to understand whether deaminases are involved in SARS-CoV-2 mutation and replication, and how the viral factors interact with deaminases to trigger these processes. Here, we show that APOBEC and ADAR deaminases act as the driving forces for SARS-CoV-2 mutagenesis, thereby blocking viral infection and production. Mechanistically, SARS-CoV-2 nucleocapsid (N) protein, which is responsible for packaging viral genomic RNA, interacts with host deaminases and co-localizes with them at stress granules to facilitate viral RNA mutagenesis. N proteins from several coronaviruses interact with host deaminases at RNA granules in a manner dependent on its F17 residue, suggesting a conserved role in modulation of viral mutagenesis in other coronaviruses. Furthermore, mutant N protein bearing a F17A substitution cannot localize to deaminase-containing RNA granules and leads to reduced mutagenesis of viral RNA, providing support for its function in enhancing deaminase-dependent viral RNA editing. Our study thus provides further insight into virus-host cell interactions mediating SARS-CoV-2 evolution.
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Affiliation(s)
- Zhean Li
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Department of Urology & Andrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lingling Luo
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Xiaohui Ju
- Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China
| | - Shisheng Huang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Liqun Lei
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Yanying Yu
- Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China
| | - Jia Liu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China
| | - Pumin Zhang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Tian Chi
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Peixiang Ma
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Guangzhou Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong, China
| | - Cheng Huang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Xingxu Huang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
| | - Qiang Ding
- Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China.
| | - Yu Zhang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China.
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Park DG, Kang W, Shin IJ, Chalita M, Oh HS, Hyun DW, Kim H, Chun J, An YS, Lee EJ, Yoon JH. Difference in gut microbial dysbiotic patterns between body-first and brain-first Parkinson's disease. Neurobiol Dis 2024; 201:106655. [PMID: 39218360 DOI: 10.1016/j.nbd.2024.106655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/31/2024] [Accepted: 08/29/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND This study aims to identify distinct microbial and functional biomarkers characteristic of body-first or brain-first subtypes of Parkinson's disease (PD). This could illuminate the unique pathogenic mechanisms within these subtypes. METHODS In this cross-sectional study, we classified 36 well-characterized PD patients into body-first, brain-first, or undetermined subtypes based on the presence of premotor REM sleep behavior disorder (RBD) and cardiac meta-iodobenzylguanidine (MIBG) uptake. We then conducted an in-depth shotgun metagenomic analysis of the gut microbiome for each subtype and compared the results with those from age- and sex-matched healthy controls. RESULTS Significant differences were found in the gut microbiome of body-first PD patients (n = 15) compared to both brain-first PD patients (n = 9) and healthy controls. The gut microbiome in body-first PD showed a distinct profile, characterized by an increased presence of Escherichia coli and Akkermansia muciniphila, and a decreased abundance of short-chain fatty acid-producing commensal bacteria. These shifts were accompanied by a higher abundance of microbial genes associated with curli protein biosynthesis and a lower abundance of genes involved in putrescine and spermidine biosynthesis. Furthermore, the combined use of premotor RBD and MIBG criteria was more strongly correlated with these microbiome differences than the use of each criterion independently. CONCLUSIONS Our findings highlight the significant role of dysbiotic and pathogenic gut microbial alterations in body-first PD, supporting the body-first versus brain-first hypothesis. These insights not only reinforce the gut microbiome's potential as a therapeutic target in PD but also suggest the possibility of developing subtype-specific treatment strategies.
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Affiliation(s)
- Don Gueu Park
- Department of Neurology, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Woorim Kang
- CJ Bioscience Inc., Seoul 04527, Republic of Korea
| | - In-Ja Shin
- Department of Neurology, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | | | - Hyun-Seok Oh
- CJ Bioscience Inc., Seoul 04527, Republic of Korea
| | | | - Hyun Kim
- CJ Bioscience Inc., Seoul 04527, Republic of Korea
| | - Jongsik Chun
- CJ Bioscience Inc., Seoul 04527, Republic of Korea
| | - Young-Sil An
- Department of Nuclear Medicine, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Eun Jeong Lee
- Department of Brain Science, Ajou University School of Medicine, Suwon 16499, Republic of Korea.
| | - Jung Han Yoon
- Department of Neurology, Ajou University School of Medicine, Suwon 16499, Republic of Korea.
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6
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Fu ZC, Gao BQ, Nan F, Ma XK, Yang L. DEMINING: A deep learning model embedded framework to distinguish RNA editing from DNA mutations in RNA sequencing data. Genome Biol 2024; 25:258. [PMID: 39380061 PMCID: PMC11463134 DOI: 10.1186/s13059-024-03397-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 09/20/2024] [Indexed: 10/10/2024] Open
Abstract
Precise calling of promiscuous adenosine-to-inosine RNA editing sites from transcriptomic datasets is hindered by DNA mutations and sequencing/mapping errors. Here, we present a stepwise computational framework, called DEMINING, to distinguish RNA editing and DNA mutations directly from RNA sequencing datasets, with an embedded deep learning model named DeepDDR. After transfer learning, DEMINING can also classify RNA editing sites and DNA mutations from non-primate sequencing samples. When applied in samples from acute myeloid leukemia patients, DEMINING uncovers previously underappreciated DNA mutation and RNA editing sites; some associated with the upregulated expression of host genes or the production of neoantigens.
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Affiliation(s)
- Zhi-Can Fu
- Center for Molecular Medicine, Children's Hospital of Fudan University and Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Bao-Qing Gao
- Center for Molecular Medicine, Children's Hospital of Fudan University and Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Fang Nan
- Center for Molecular Medicine, Children's Hospital of Fudan University and Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Xu-Kai Ma
- Center for Molecular Medicine, Children's Hospital of Fudan University and Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Li Yang
- Center for Molecular Medicine, Children's Hospital of Fudan University and Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
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7
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Chatterjee P, Ghosal P, Shit S, Biswas A, Mallik S, Allabun S, Othman M, Ali AH, Elshiekh E, Soufiene BO. Ribosomal computing: implementation of the computational method. BMC Bioinformatics 2024; 25:321. [PMID: 39358680 PMCID: PMC11448306 DOI: 10.1186/s12859-024-05945-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Several computational and mathematical models of protein synthesis have been explored to accomplish the quantitative analysis of protein synthesis components and polysome structure. The effect of gene sequence (coding and non-coding region) in protein synthesis, mutation in gene sequence, and functional model of ribosome needs to be explored to investigate the relationship among protein synthesis components further. Ribosomal computing is implemented by imitating the functional property of protein synthesis. RESULT In the proposed work, a general framework of ribosomal computing is demonstrated by developing a computational model to present the relationship between biological details of protein synthesis and computing principles. Here, mathematical abstractions are chosen carefully without probing into intricate chemical details of the micro-operations of protein synthesis for ease of understanding. This model demonstrates the cause and effect of ribosome stalling during protein synthesis and the relationship between functional protein and gene sequence. Moreover, it also reveals the computing nature of ribosome molecules and other protein synthesis components. The effect of gene mutation on protein synthesis is also explored in this model. CONCLUSION The computational model for ribosomal computing is implemented in this work. The proposed model demonstrates the relationship among gene sequences and protein synthesis components. This model also helps to implement a simulation environment (a simulator) for generating protein chains from gene sequences and can spot the problem during protein synthesis. Thus, this simulator can identify a disease that can happen due to a protein synthesis problem and suggest precautions for it.
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Affiliation(s)
| | | | - Sahadeb Shit
- Kazi Nazrul University, Asansol, West Bengal, India
| | | | - Saurav Mallik
- Department of Environmental Health, Harvard T H Chan School of Public Health, Boston, USA
- Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ, 02115, USA
| | - Sarah Allabun
- Department of Medical Education, College of Medicine, Princess Nourah bint Abdulrahman University, P.O.Box 84428, Riyadh, 11671, Saudi Arabia
| | - Manal Othman
- Department of Medical Education, College of Medicine, Princess Nourah bint Abdulrahman University, P.O.Box 84428, Riyadh, 11671, Saudi Arabia
| | - Almubarak Hassan Ali
- Division of Radiology, Department of Medicine, College of Medicine and surgery, King Khalid University (KKU), Abha, Aseer, Kingdom of Saudi Arabia
| | - E Elshiekh
- Department of Radiological Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Ben Othman Soufiene
- PRINCE Laboratory Research, ISITcom, Hammam Sousse, University of Sousse, Sousse, Tunisia.
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Zhao H, Wu Z, Wang Z, Ru J, Wang S, Li Y, Hou S, Zhang Y, Wang X. Genomic Landscape and Regulation of RNA Editing in Pekin Ducks Susceptible to Duck Hepatitis A Virus Genotype 3 Infection. Int J Mol Sci 2024; 25:10413. [PMID: 39408741 PMCID: PMC11476845 DOI: 10.3390/ijms251910413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 09/25/2024] [Accepted: 09/26/2024] [Indexed: 10/20/2024] Open
Abstract
RNA editing is increasingly recognized as a post-transcriptional modification that directly affects viral infection by regulating RNA stability and recoding proteins. the duck hepatitis A virus genotype 3 (DHAV-3) infection is seriously detrimental to the Asian duck industry. However, the landscape and roles of RNA editing in the susceptibility and resistance of Pekin ducks to DHAV-3 remain unclear. Here, we profiled dynamic RNA editing events in liver tissue and investigated their potential functions during DHAV-3 infection in Pekin ducks. We identified 11,067 informative RNA editing sites in liver tissue from DHAV-3-susceptible and -resistant ducklings at three time points during virus infection. Differential RNA editing sites (DRESs) between S and R ducks were dynamically changed during infection, which were enriched in genes associated with vesicle-mediated transport and immune-related pathways. Moreover, we predicted and experimentally verified that RNA editing events in 3'-UTR could result in loss or gain of miRNA-mRNA interactions, thereby changing the expression of target genes. We also found a few DRESs in coding sequences (CDSs) that altered the amino acid sequences of several proteins that were vital for viral infection. Taken together, these data suggest that dynamic RNA editing has significant potential to tune physiological processes in response to virus infection in Pekin ducks, thus contributing to host differential susceptibility to DHAV-3.
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Affiliation(s)
- Haonao Zhao
- College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China; (H.Z.); (Z.W.); (Z.W.); (J.R.); (Y.L.)
| | - Zifang Wu
- College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China; (H.Z.); (Z.W.); (Z.W.); (J.R.); (Y.L.)
| | - Zezhong Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China; (H.Z.); (Z.W.); (Z.W.); (J.R.); (Y.L.)
| | - Jinlong Ru
- College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China; (H.Z.); (Z.W.); (Z.W.); (J.R.); (Y.L.)
| | - Shuaiqin Wang
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (S.W.); (S.H.)
| | - Yang Li
- College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China; (H.Z.); (Z.W.); (Z.W.); (J.R.); (Y.L.)
| | - Shuisheng Hou
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (S.W.); (S.H.)
| | - Yunsheng Zhang
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (S.W.); (S.H.)
| | - Xia Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China; (H.Z.); (Z.W.); (Z.W.); (J.R.); (Y.L.)
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Leonard AS, Mapel XM, Pausch H. RNA-DNA differences in variant calls from cattle tissues result in erroneous eQTLs. BMC Genomics 2024; 25:750. [PMID: 39090567 PMCID: PMC11295900 DOI: 10.1186/s12864-024-10645-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 07/22/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Association testing between molecular phenotypes and genomic variants can help to understand how genotype affects phenotype. RNA sequencing provides access to molecular phenotypes such as gene expression and alternative splicing while DNA sequencing or microarray genotyping are the prevailing options to obtain genomic variants. RESULTS We genotype variants for 74 male Braunvieh cattle from both DNA (~ 13-fold coverage) and deep total RNA sequencing from testis, vas deferens, and epididymis tissue (~ 250 million reads per tissue). We show that RNA sequencing can be used to identify approximately 40% of variants (7-10 million) called from DNA sequencing, with over 80% precision. Within highly expressed coding regions, over 92% of expected variants were called with nearly 98% precision. Allele-specific expression and putative post-transcriptional modifications negatively impact variant genotyping accuracy from RNA sequencing and contribute to RNA-DNA differences. Variants called from RNA sequencing detect roughly 75% of eGenes identified using variants called from DNA sequencing, demonstrating a nearly 2-fold enrichment of eQTL variants. We observe a moderate-to-strong correlation in nominal association p-values (Spearman ρ2 ~ 0.6), although only 9% of eGenes have the same top associated variant. CONCLUSIONS We find hundreds of thousands of RNA-DNA differences in variants called from RNA and DNA sequencing on the same individuals. We identify several highly significant eQTL when using RNA sequencing variant genotypes which are not found with DNA sequencing variant genotypes, suggesting that using RNA sequencing variant genotypes for association testing results in an increased number of false positives. Our findings demonstrate that caution must be exercised beyond filtering for variant quality or imputation accuracy when analysing or imputing variants called from RNA sequencing.
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Affiliation(s)
- Alexander S Leonard
- Animal Genomics, ETH Zurich, Universitaetstrasse 2, Zurich, 8092, Switzerland.
| | - Xena M Mapel
- Animal Genomics, ETH Zurich, Universitaetstrasse 2, Zurich, 8092, Switzerland
| | - Hubert Pausch
- Animal Genomics, ETH Zurich, Universitaetstrasse 2, Zurich, 8092, Switzerland.
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10
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Bernal YA, Durán E, Solar I, Sagredo EA, Armisén R. ADAR-Mediated A>I(G) RNA Editing in the Genotoxic Drug Response of Breast Cancer. Int J Mol Sci 2024; 25:7424. [PMID: 39000531 PMCID: PMC11242177 DOI: 10.3390/ijms25137424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 06/13/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Epitranscriptomics is a field that delves into post-transcriptional changes. Among these modifications, the conversion of adenosine to inosine, traduced as guanosine (A>I(G)), is one of the known RNA-editing mechanisms, catalyzed by ADARs. This type of RNA editing is the most common type of editing in mammals and contributes to biological diversity. Disruption in the A>I(G) RNA-editing balance has been linked to diseases, including several types of cancer. Drug resistance in patients with cancer represents a significant public health concern, contributing to increased mortality rates resulting from therapy non-responsiveness and disease progression, representing the greatest challenge for researchers in this field. The A>I(G) RNA editing is involved in several mechanisms over the immunotherapy and genotoxic drug response and drug resistance. This review investigates the relationship between ADAR1 and specific A>I(G) RNA-edited sites, focusing particularly on breast cancer, and the impact of these sites on DNA damage repair and the immune response over anti-cancer therapy. We address the underlying mechanisms, bioinformatics, and in vitro strategies for the identification and validation of A>I(G) RNA-edited sites. We gathered databases related to A>I(G) RNA editing and cancer and discussed the potential clinical and research implications of understanding A>I(G) RNA-editing patterns. Understanding the intricate role of ADAR1-mediated A>I(G) RNA editing in breast cancer holds significant promise for the development of personalized treatment approaches tailored to individual patients' A>I(G) RNA-editing profiles.
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Affiliation(s)
- Yanara A Bernal
- Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina (ICIM), Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago 7610658, Chile
| | - Eduardo Durán
- Subdepartamento de Genómica y Genética Molecular, Sección Genética Humana, Instituto de Salud Pública de Chile, Avenida Marathon 1000, Ñuñoa, Santiago 7780050, Chile
| | - Isidora Solar
- Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina (ICIM), Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago 7610658, Chile
| | - Eduardo A Sagredo
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 77 Stockholm, Sweden
- Science for Life Laboratory, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-171 77 Stockholm, Sweden
| | - Ricardo Armisén
- Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina (ICIM), Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago 7610658, Chile
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11
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XIONG J, FENG T, YUAN BF. [Advances in mapping analysis of ribonucleic acid modifications through sequencing]. Se Pu 2024; 42:632-645. [PMID: 38966972 PMCID: PMC11224946 DOI: 10.3724/sp.j.1123.2023.12025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Indexed: 07/06/2024] Open
Abstract
Over 170 chemical modifications have been discovered in various types of ribonucleic acids (RNAs), including messenger RNA (mRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), and small nuclear RNA (snRNA). These RNA modifications play crucial roles in a wide range of biological processes such as gene expression regulation, RNA stability maintenance, and protein translation. RNA modifications represent a new dimension of gene expression regulation known as the "epitranscriptome". The discovery of RNA modifications and the relevant writers, erasers, and readers provides an important basis for studies on the dynamic regulation and physiological functions of RNA modifications. Owing to the development of detection technologies for RNA modifications, studies on RNA epitranscriptomes have progressed to the single-base resolution, multilayer, and full-coverage stage. Transcriptome-wide methods help discover new RNA modification sites and are of great importance for elucidating the molecular regulatory mechanisms of epitranscriptomics, exploring the disease associations of RNA modifications, and understanding their clinical applications. The existing RNA modification sequencing technologies can be categorized according to the pretreatment approach and sequencing principle as direct high-throughput sequencing, antibody-enrichment sequencing, enzyme-assisted sequencing, chemical labeling-assisted sequencing, metabolic labeling sequencing, and nanopore sequencing technologies. These methods, as well as studies on the functions of RNA modifications, have greatly expanded our understanding of epitranscriptomics. In this review, we summarize the recent progress in RNA modification detection technologies, focusing on the basic principles, advantages, and limitations of different methods. Direct high-throughput sequencing methods do not require complex RNA pretreatment and allow for the mapping of RNA modifications using conventional RNA sequencing methods. However, only a few RNA modifications can be analyzed by high-throughput sequencing. Antibody enrichment followed by high-throughput sequencing has emerged as a crucial approach for mapping RNA modifications, significantly advancing the understanding of RNA modifications and their regulatory functions in different species. However, the resolution of antibody-enrichment sequencing is limited to approximately 100-200 bp. Although chemical crosslinking techniques can achieve single-base resolution, these methods are often complex, and the specificity of the antibodies used in these methods has raised concerns. In particular, the issue of off-target binding by the antibodies requires urgent attention. Enzyme-assisted sequencing has improved the accuracy of the localization analysis of RNA modifications and enables stoichiometric detection with single-base resolution. However, the enzymes used in this technique show poor reactivity, specificity, and sequence preference. Chemical labeling sequencing has become a widely used approach for profiling RNA modifications, particularly by altering reverse transcription (RT) signatures such as RT stops, misincorporations, and deletions. Chemical-assisted sequencing provides a sequence-independent RNA modification detection strategy that enables the localization of multiple RNA modifications. Additionally, when combined with the biotin-streptavidin affinity method, low-abundance RNA modifications can be enriched and detected. Nevertheless, the specificity of many chemical reactions remains problematic, and the development of specific reaction probes for particular modifications should continue in the future to achieve the precise localization of RNA modifications. As an indirect localization method, metabolic labeling sequencing specifically localizes the sites at which modifying enzymes act, which is of great significance in the study of RNA modification functions. However, this method is limited by the intracellular labeling of RNA and cannot be applied to biological samples such as clinical tissues and blood samples. Nanopore sequencing is a direct RNA-sequencing method that does not require RT or the polymerase chain reaction (PCR). However, challenges in analyzing the data obtained from nanopore sequencing, such as the high rate of false positives, must be resolved. Discussing sequencing analysis methods for various types of RNA modifications is instructive for the future development of novel RNA modification mapping technologies, and will aid studies on the functions of RNA modifications across the entire transcriptome.
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12
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Kose C, Lindsey-Boltz LA, Sancar A, Jiang Y. Genome-wide analysis of transcription-coupled repair reveals novel transcription events in Caenorhabditis elegans. PLoS Genet 2024; 20:e1011365. [PMID: 39028758 PMCID: PMC11290646 DOI: 10.1371/journal.pgen.1011365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 07/31/2024] [Accepted: 07/08/2024] [Indexed: 07/21/2024] Open
Abstract
Bulky DNA adducts such as those induced by ultraviolet light are removed from the genomes of multicellular organisms by nucleotide excision repair, which occurs through two distinct mechanisms, global repair, requiring the DNA damage recognition-factor XPC (xeroderma pigmentosum complementation group C), and transcription-coupled repair (TCR), which does not. TCR is initiated when elongating RNA polymerase II encounters DNA damage, and thus analysis of genome-wide excision repair in XPC-mutants only repairing by TCR provides a unique opportunity to map transcription events missed by methods dependent on capturing RNA transcription products and thus limited by their stability and/or modifications (5'-capping or 3'-polyadenylation). Here, we have performed eXcision Repair-sequencing (XR-seq) in the model organism Caenorhabditis elegans to generate genome-wide repair maps in a wild-type strain with normal excision repair, a strain lacking TCR (csb-1), and a strain that only repairs by TCR (xpc-1). Analysis of the intersections between the xpc-1 XR-seq repair maps with RNA-mapping datasets (RNA-seq, long- and short-capped RNA-seq) reveal previously unrecognized sites of transcription and further enhance our understanding of the genome of this important model organism.
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Affiliation(s)
- Cansu Kose
- Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Laura A. Lindsey-Boltz
- Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Aziz Sancar
- Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Yuchao Jiang
- Department of Statistics, College of Arts and Sciences, Texas A&M University, College Station, Texas, United States of America
- Department of Biology, College of Arts and Sciences, Texas A&M University, College Station, Texas, United States of America
- Department of Biomedical Engineering, College of Engineering, Texas A&M University, College Station, Texas, United States of America
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Chen C, Bundschuh R. A-to-I Editing Is Subtype-Specific in Non-Hodgkin Lymphomas. Genes (Basel) 2024; 15:864. [PMID: 39062643 PMCID: PMC11276283 DOI: 10.3390/genes15070864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 06/25/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024] Open
Abstract
Cancer is a complex and heterogeneous disease, in which a number of genetic and epigenetic changes occur in tumor onset and progression. Recent studies indicate that changes at the RNA level are also involved in tumorigenesis, such as adenosine-to-inosine (A-to-I) RNA editing. Here, we systematically investigate transcriptome-wide A-to-I editing events in a large number of samples from Non-Hodgkin lymphomas (NHLs). Using a computational pipeline that determines significant differences in editing level between NHL and normal samples at known A-to-I editing sites, we identify a number of differentially edited editing sites between NHL subtypes and normal samples. Most of the differentially edited sites are located in non-coding regions, and many such sites show a strong correlation between gene expression level and editing efficiency, indicating that RNA editing might have direct consequences for the cancer cell's aberrant gene regulation status in these cases. Moreover, we establish a strong link between RNA editing and NHL by demonstrating that NHL and normal samples and even NHL subtypes can be distinguished based on genome-wide RNA editing profiles alone. Our study establishes a strong link between RNA editing, cancer and aberrant gene regulation in NHL.
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Affiliation(s)
- Cai Chen
- Biophysics Graduate Program, The Ohio State University, Columbus, OH 43210, USA
- Center for RNA Biology, The Ohio State University, Columbus, OH 43210, USA
| | - Ralf Bundschuh
- Biophysics Graduate Program, The Ohio State University, Columbus, OH 43210, USA
- Center for RNA Biology, The Ohio State University, Columbus, OH 43210, USA
- Department of Physics, The Ohio State University, Columbus, OH 43210, USA
- Department of Chemistry & Biochemistry, The Ohio State University, Columbus, OH 43210, USA
- Division of Hematology, The Ohio State University, Columbus, OH 43210, USA
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14
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Yoon HJ, Kang W, Jo S, Hwang YS, Lee JH, Chung SJ, Park YK. Dietary quality and the gut microbiome in early-stage Parkinson's disease patients. Nutr Neurosci 2024; 27:761-769. [PMID: 37711026 DOI: 10.1080/1028415x.2023.2253025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/16/2023]
Abstract
BACKGROUND The prevalence of Parkinson's disease (PD) has increased steadily with the increase of the elderly population. PD may influence dietary intake and quality, and the gut microbiome composition. The present study examined differences in dietary intake and quality between PD patients and controls according to sex. In addition, we assessed the gut microbiome composition. METHODS This cross-sectional study was conducted at A Medical Center, Seoul, South Korea. PD severity, swallowing function, olfactory function, and constipation status were examined by a skilled nurse. Dietary data were collected through a semi-quantitative food frequency questionnaire. Stool samples were subjected to microbiome analysis. To examine dietary quality, the Dietary Quality Index-International (DQI-I), Healthy Eating Index (HEI), Index of Nutritional Quality (INQ), Dietary Diversity Score (DDS), and Mediterranean Diet Score (MDS) were used. An independent t-test was used to determine differences between patients and controls. A chi-square test was used to examine frequency differences. RESULTS Dietary intake did not differ between the PD patient and control groups. Regarding dietary quality, the patients consumed more saturated fat compared to controls. Overall, the dietary differences between the groups were minor. The composition of the gut microbiome differed between PD patients and controls. Lactobacillus and Bifidobacterium genus were most abundant in PD patients. Prevotella VZCB and other Faecalibacterium were most abundant in controls. CONCLUSIONS Our results indicated that PD patients may experience gut microbiome change even in the early stage, while nutritional needs can be met when a balanced diet including various food groups are consumed.
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Affiliation(s)
- Hyun Jeong Yoon
- Department of Medical Nutrition, Graduate School of East-West Medical Science, Kyung Hee University, Yongin, South Korea
| | - Woorim Kang
- Department of Biology and Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, South Korea
- Department of Drug Development, Development center, CJ Bioscience Inc., Seoul, South Korea
| | - Sungyang Jo
- Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yun Su Hwang
- Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Je Hee Lee
- Department of Drug Development, Development center, CJ Bioscience Inc., Seoul, South Korea
| | - Sun Ju Chung
- Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yoo Kyoung Park
- Department of Medical Nutrition, Graduate School of East-West Medical Science, Kyung Hee University, Yongin, South Korea
- Department of Medical Nutrition (AgeTech-Service Convergence Major), Kyung Hee University, Yongin, South Korea
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15
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Cottrell KA, Ryu S, Pierce JR, Soto Torres L, Bohlin HE, Schab AM, Weber JD. Induction of Viral Mimicry Upon Loss of DHX9 and ADAR1 in Breast Cancer Cells. CANCER RESEARCH COMMUNICATIONS 2024; 4:986-1003. [PMID: 38530197 PMCID: PMC10993856 DOI: 10.1158/2767-9764.crc-23-0488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 01/24/2024] [Accepted: 03/19/2024] [Indexed: 03/27/2024]
Abstract
Detection of viral double-stranded RNA (dsRNA) is an important component of innate immunity. However, many endogenous RNAs containing double-stranded regions can be misrecognized and activate innate immunity. The IFN-inducible ADAR1-p150 suppresses dsRNA sensing, an essential function for adenosine deaminase acting on RNA 1 (ADAR1) in many cancers, including breast. Although ADAR1-p150 has been well established in this role, the functions of the constitutively expressed ADAR1-p110 isoform are less understood. We used proximity labeling to identify putative ADAR1-p110-interacting proteins in breast cancer cell lines. Of the proteins identified, the RNA helicase DHX9 was of particular interest. Knockdown of DHX9 in ADAR1-dependent cell lines caused cell death and activation of the dsRNA sensor PKR. In ADAR1-independent cell lines, combined knockdown of DHX9 and ADAR1, but neither alone, caused activation of multiple dsRNA sensing pathways leading to a viral mimicry phenotype. Together, these results reveal an important role for DHX9 in suppressing dsRNA sensing by multiple pathways. SIGNIFICANCE These findings implicate DHX9 as a suppressor of dsRNA sensing. In some cell lines, loss of DHX9 alone is sufficient to cause activation of dsRNA sensing pathways, while in other cell lines DHX9 functions redundantly with ADAR1 to suppress pathway activation.
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Affiliation(s)
- Kyle A. Cottrell
- Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri
- ICCE Institute, Washington University School of Medicine, St. Louis, Missouri
- Department of Biochemistry, Purdue University, West Lafayette, Indiana
| | - Sua Ryu
- Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri
- ICCE Institute, Washington University School of Medicine, St. Louis, Missouri
| | - Jackson R. Pierce
- Department of Biochemistry, Purdue University, West Lafayette, Indiana
| | - Luisangely Soto Torres
- Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri
- ICCE Institute, Washington University School of Medicine, St. Louis, Missouri
| | - Holly E. Bohlin
- Department of Biochemistry, Purdue University, West Lafayette, Indiana
| | - Angela M. Schab
- Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri
- ICCE Institute, Washington University School of Medicine, St. Louis, Missouri
| | - Jason D. Weber
- Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri
- ICCE Institute, Washington University School of Medicine, St. Louis, Missouri
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri
- Department of Biology, Siteman Cancer Center, St. Louis, Missouri
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16
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Kose C, Lindsey-Boltz LA, Sancar A, Jiang Y. Genome-wide analysis of transcription-coupled repair reveals novel transcription events in Caenorhabditis elegans. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.10.12.562083. [PMID: 37904932 PMCID: PMC10614815 DOI: 10.1101/2023.10.12.562083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/01/2023]
Abstract
Bulky DNA adducts such as those induced by ultraviolet light are removed from the genomes of multicellular organisms by nucleotide excision repair, which occurs through two distinct mechanisms, global repair, requiring the DNA damage recognition-factor XPC (xeroderma pigmentosum complementation group C), and transcription-coupled repair (TCR), which does not. TCR is initiated when elongating RNA polymerase II encounters DNA damage, and thus analysis of genome-wide excision repair in XPC-mutants only repairing by TCR provides a unique opportunity to map transcription events missed by methods dependent on capturing RNA transcription products and thus limited by their stability and/or modifications (5'-capping or 3'-polyadenylation). Here, we have performed the eXcision Repair-sequencing (XR-seq) in the model organism Caenorhabditis elegans to generate genome-wide repair maps from a wild-type strain with normal excision repair, a strain lacking TCR (csb-1), or one that only repairs by TCR (xpc-1). Analysis of the intersections between the xpc-1 XR-seq repair maps with RNA-mapping datasets (RNA-seq, long- and short-capped RNA-seq) reveal previously unrecognized sites of transcription and further enhance our understanding of the genome of this important model organism.
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Affiliation(s)
- Cansu Kose
- Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Laura A. Lindsey-Boltz
- Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Aziz Sancar
- Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Yuchao Jiang
- Department of Statistics, College of Arts and Sciences, Texas A&M University, College Station, TX 77843, USA
- Department of Biology, College of Arts and Sciences, Texas A&M University, College Station, TX 77843
- Department of Biomedical Engineering, College of Engineering, Texas A&M University, College Station, TX 77843
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17
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Li J, Li C, Xu W. Liver cancer-specific mutations in functional domains of ADAR2 lead to the elevation of coding and non-coding RNA editing in multiple tumor-related genes. Mol Genet Genomics 2024; 299:1. [PMID: 38170228 DOI: 10.1007/s00438-023-02091-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 10/17/2023] [Indexed: 01/05/2024]
Abstract
Mutation is the major cause of phenotypic innovations. Apart from DNA mutations, the alteration on RNA such as the ADAR-mediated A-to-I RNA editing could also shape the phenotype. These two layers of variations have not been systematically combined to study their collective roles in cancers. We collected the high-quality transcriptomes of ten hepatocellular carcinoma (HCC) and the matched control samples. We systematically identified HCC-specific mutations in the exonic regions and profiled the A-to-I RNA editome in each sample. All ten HCC samples had mutations in the CDS of ADAR2 gene (dsRNA-binding domain or catalytic domain). The consequence of these mutations converged to the elevation of ADAR2 efficiency as reflected by the global increase of RNA editing levels in HCC. The up-regulated editing sites (UES) were enriched in the CDS and UTR of oncogenes and tumor suppressor genes (TSG), indicating the possible roles of these target genes in HCC oncogenesis. We present the mutation-ADAR2-UES-oncogene/TSG-HCC axis that explains how mutations at different layers would finally lead to abnormal phenotype. In the light of central dogma, our work provides novel insights into how to fully take advantage of the transcriptome data to decipher the consequence of mutations.
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Affiliation(s)
- Jian Li
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Chaowei Li
- Department of PET/CT, The Second Clinical Medical College of Qingdao University (Qingdao Center Hospital), Qingdao, 266042, China
| | - Wengui Xu
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
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18
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Liu J, Zhao T, Zheng C, Ma L, Song F, Tian L, Cai W, Li H, Duan Y. An orthology-based methodology as a complementary approach to retrieve evolutionarily conserved A-to-I RNA editing sites. RNA Biol 2024; 21:29-45. [PMID: 39256954 PMCID: PMC11404581 DOI: 10.1080/15476286.2024.2397757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 08/14/2024] [Accepted: 08/19/2024] [Indexed: 09/12/2024] Open
Abstract
Adar-mediated adenosine-to-inosine (A-to-I) mRNA editing is a conserved mechanism that exerts diverse regulatory functions during the development, evolution, and adaptation of metazoans. The accurate detection of RNA editing sites helps us understand their biological significance. In this work, with an improved genome assembly of honeybee (Apis mellifera), we used a new orthology-based methodology to complement the traditional pipeline of (de novo) RNA editing detection. Compared to the outcome of traditional pipeline, we retrieved many novel editing sites in CDS that are deeply conserved between honeybee and other distantly related insects. The newly retrieved sites were missed by the traditional de novo identification due to the stringent criteria for controlling false-positive rate. Caste-specific editing sites are identified, including an Ile>Met auto-recoding site in Adar. This recoding was even conserved between honeybee and bumblebee, suggesting its putative regulatory role in shaping the phenotypic plasticity of eusocial Hymenoptera. In summary, we proposed a complementary approach to the traditional pipeline and retrieved several previously unnoticed CDS editing sites. From both technical and biological aspects, our works facilitate future researches on finding the functional editing sites and advance our understanding on the connection between RNA editing and the great phenotypic diversity of organisms.
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Affiliation(s)
- Jiyao Liu
- Department of Entomology and MOA Key Lab of Pest Monitoring and Green Management, College of Plant Protection, China Agricultural University, Beijing, China
| | - Tianyou Zhao
- Department of Entomology and MOA Key Lab of Pest Monitoring and Green Management, College of Plant Protection, China Agricultural University, Beijing, China
| | - Caiqing Zheng
- Department of Entomology and MOA Key Lab of Pest Monitoring and Green Management, College of Plant Protection, China Agricultural University, Beijing, China
| | - Ling Ma
- Department of Entomology and MOA Key Lab of Pest Monitoring and Green Management, College of Plant Protection, China Agricultural University, Beijing, China
| | - Fan Song
- Department of Entomology and MOA Key Lab of Pest Monitoring and Green Management, College of Plant Protection, China Agricultural University, Beijing, China
| | - Li Tian
- Department of Entomology and MOA Key Lab of Pest Monitoring and Green Management, College of Plant Protection, China Agricultural University, Beijing, China
| | - Wanzhi Cai
- Department of Entomology and MOA Key Lab of Pest Monitoring and Green Management, College of Plant Protection, China Agricultural University, Beijing, China
| | - Hu Li
- Department of Entomology and MOA Key Lab of Pest Monitoring and Green Management, College of Plant Protection, China Agricultural University, Beijing, China
| | - Yuange Duan
- Department of Entomology and MOA Key Lab of Pest Monitoring and Green Management, College of Plant Protection, China Agricultural University, Beijing, China
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19
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GWAK SEUNGHEE, LEE JUHYUN, OH EUNJI, LEE DOHYUN, HAN WONSHIK, KIM JONGMIN, KIM KYONGTAI. Vaccinia-related kinase 2 variants differentially affect breast cancer growth by regulating kinase activity. Oncol Res 2023; 32:421-432. [PMID: 38186576 PMCID: PMC10765118 DOI: 10.32604/or.2023.031031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/03/2023] [Indexed: 01/09/2024] Open
Abstract
Genetic information is transcribed from genomic DNA to mRNA, which is then translated into three-dimensional proteins. mRNAs can undergo various post-transcriptional modifications, including RNA editing that alters mRNA sequences, ultimately affecting protein function. In this study, RNA editing was identified at the 499th base (c.499) of human vaccinia-related kinase 2 (VRK2). This RNA editing changes the amino acid in the catalytic domain of VRK2 from isoleucine (with adenine base) to valine (with guanine base). Isoleucine-containing VRK2 has higher kinase activity than the valine-containing VRK2, which leads to an increase in tumor cell proliferation. Earlier we reported that VRK2 directly interacts with dystrobrevin-binding protein (dysbindin) and results in reducing its stability. Herein, we demonstrate that isoleucine-containing VRK2 decreases the level of dysbindin than valine-containing VRK2. Dysbindin interacts with cyclin D and thereby regulates its expression and function. The reduction in the level of dysbindin by isoleucine-containing VRK2 further enhances the cyclin D expression, resulting in increased tumor growth and reduction in survival rates. It has also been observed that in patient samples, VRK2 level was elevated in breast cancer tissue compared to normal breast tissue. Additionally, the isoleucine form of VRK2 exhibited a greater increase in breast cancer tissue. Therefore, it is concluded that VRK2, especially dependent on the 167th variant amino acid, can be one of the indexes of tumor progression and proliferation.
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Affiliation(s)
- SEUNG-HEE GWAK
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Korea
| | - JUHYUN LEE
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Korea
| | - EUNJI OH
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Korea
| | - DOHYUN LEE
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Korea
- R&D Center, NovMetaPharma Co., Ltd., Pohang, 37668, Korea
| | - WONSHIK HAN
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, 03080, Korea
| | - JONGMIN KIM
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Korea
| | - KYONG-TAI KIM
- Generative Genomics Research Center, Global Green Research & Development Center, Handong Global University, Pohang, 37554, Korea
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Xu Y, Liu J, Zhao T, Song F, Tian L, Cai W, Li H, Duan Y. Identification and Interpretation of A-to-I RNA Editing Events in Insect Transcriptomes. Int J Mol Sci 2023; 24:17126. [PMID: 38138955 PMCID: PMC10742984 DOI: 10.3390/ijms242417126] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 12/01/2023] [Accepted: 12/03/2023] [Indexed: 12/24/2023] Open
Abstract
Adenosine-to-inosine (A-to-I) RNA editing is the most prevalent RNA modification in the nervous systems of metazoans. To study the biological significance of RNA editing, we first have to accurately identify these editing events from the transcriptome. The genome-wide identification of RNA editing sites remains a challenging task. In this review, we will first introduce the occurrence, regulation, and importance of A-to-I RNA editing and then describe the established bioinformatic procedures and difficulties in the accurate identification of these sit esespecially in small sized non-model insects. In brief, (1) to obtain an accurate profile of RNA editing sites, a transcriptome coupled with the DNA resequencing of a matched sample is favorable; (2) the single-cell sequencing technique is ready to be applied to RNA editing studies, but there are a few limitations to overcome; (3) during mapping and variant calling steps, various issues, like mapping and base quality, soft-clipping, and the positions of mismatches on reads, should be carefully considered; (4) Sanger sequencing of both RNA and the matched DNA is the best verification of RNA editing sites, but other auxiliary evidence, like the nonsynonymous-to-synonymous ratio or the linkage information, is also helpful for judging the reliability of editing sites. We have systematically reviewed the understanding of the biological significance of RNA editing and summarized the methodology for identifying such editing events. We also raised several promising aspects and challenges in this field. With insightful perspectives on both scientific and technical issues, our review will benefit the researchers in the broader RNA editing community.
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Affiliation(s)
| | | | | | | | | | | | | | - Yuange Duan
- MOA Key Lab of Pest Monitoring and Green Management, Department of Entomology, College of Plant Protection, China Agricultural University, Beijing 100193, China; (Y.X.); (J.L.); (T.Z.); (F.S.); (L.T.); (W.C.); (H.L.)
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21
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Tan MH. Identification of Bona Fide RNA Editing Sites: History, Challenges, and Opportunities. Acc Chem Res 2023; 56:3033-3044. [PMID: 37827987 DOI: 10.1021/acs.accounts.3c00462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2023]
Abstract
Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by the adenosine deaminase acting on the RNA (ADAR) family of enzymes of which there are three members (ADAR1, ADAR2, and ADAR3), is a major gene regulatory mechanism that diversifies the transcriptome. It is widespread in many metazoans, including humans. As inosine is interpreted by cellular machineries mainly as guanosine, A-to-I editing effectively gives A-to-G nucleotide changes. Depending on its location, an editing event can generate new protein isoforms or influence other RNA processing pathways. Researchers have found that ADAR-mediated editing performs diverse functions. For example, it enables living organisms such as cephalopods to adapt rapidly to fluctuating environmental conditions such as water temperature. In development, the loss of ADAR1 is embryonically lethal partly because endogenous double-stranded RNAs (dsRNAs) are no longer marked by inosines, which signal "self", and thus cause the melanoma differentiation-associated protein 5 (MDA5) sensor to trigger a deleterious interferon response. Hence, ADAR1 plays a key role in preventing aberrant activation of the innate immune system. Furthermore, ADAR enzymes have been implicated in myriad human diseases. Intriguingly, some cancer cells are known to exploit ADAR1 activity to dodge immune responses. However, the exact identities of immunogenic RNAs in different biological contexts have remained elusive. Consequently, there is tremendous interest in identifying inosine-containing RNAs in the cell.The identification of A-to-I RNA editing sites is dependent on the sequencing of nucleic acids. Technological and algorithmic advancements over the past decades have revolutionized the way editing events are detected. At the beginning, the discovery of editing sites relies on Sanger sequencing, a first-generation technology. Both RNA, which is reverse transcribed into complementary DNA (cDNA), and genomic DNA (gDNA) from the same source are analyzed. After sequence alignment, one would require an adenosine to be present in the genome but a guanosine to be detected in the RNA sample for a position to be declared as an editing site. However, an issue with Sanger sequencing is its low throughput. Subsequently, Illumina sequencing, a second-generation technology, was invented. By permitting the simultaneous interrogation of millions of molecules, it enables many editing sites to be identified rapidly. However, a key challenge is that the Illumina platform produces short sequencing reads that can be difficult to map accurately. To tackle the challenge, we and others developed computational workflows with a series of filters to discard sites that are likely to be false positives. When Illumina sequencing data sets are properly analyzed, A-to-G variants should emerge as the most dominant mismatch type. Moreover, the quantitative nature of the data allows us to build a comprehensive atlas of editing-level measurements across different biological contexts, providing deep insights into the spatiotemporal dynamics of RNA editing. However, difficulties remain in identifying true A-to-I editing sites in short protein-coding exons or in organisms and diseases where DNA mutations and genomic polymorphisms are prevalent and mostly unknown. Nanopore sequencing, a third-generation technology, promises to address the difficulties, as it allows native RNAs to be sequenced without conversion to cDNA, preserving base modifications that can be directly detected through machine learning. We recently demonstrated that nanopore sequencing could be used to identify A-to-I editing sites in native RNA directly. Although further work is needed to enhance the detection accuracy in single molecules from fewer cells, the nanopore technology holds the potential to revolutionize epitranscriptomic studies.
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Affiliation(s)
- Meng How Tan
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore 637459, Singapore
- HP-NTU Digital Manufacturing Corporate Laboratory, Nanyang Technological University, Singapore 637460, Singapore
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22
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Cottrell KA, Ryu S, Torres LS, Schab AM, Weber JD. Induction of viral mimicry upon loss of DHX9 and ADAR1 in breast cancer cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.27.530307. [PMID: 36909617 PMCID: PMC10002699 DOI: 10.1101/2023.02.27.530307] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
Detection of viral double-stranded RNA (dsRNA) is an important component of innate immunity. However, many endogenous RNAs containing double-stranded regions can be misrecognized and activate innate immunity. The interferon inducible ADAR1-p150 suppresses dsRNA sensing, an essential function for ADAR1 in many cancers, including breast. Although ADAR1-p150 has been well established in this role, the functions of the constitutively expressed ADAR1-p110 isoform are less understood. We used proximity labeling to identify putative ADAR1-p110 interacting proteins in breast cancer cell lines. Of the proteins identified, the RNA helicase DHX9 was of particular interest. Knockdown of DHX9 in ADAR1-dependent cell lines caused cell death and activation of the dsRNA sensor PKR. In ADAR1-independent cell lines, combined knockdown of DHX9 and ADAR1, but neither alone, caused activation of multiple dsRNA sensing pathways leading to a viral mimicry phenotype. Together, these results reveal an important role for DHX9 in suppressing dsRNA sensing by multiple pathways.
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Affiliation(s)
- Kyle A. Cottrell
- Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, Saint Louis, Missouri, USA
- ICCE Institute, Washington University School of Medicine, Saint Louis, Missouri, USA
- Department of Biochemistry, Purdue University, West Lafayette, IN, USA
| | - Sua Ryu
- Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, Saint Louis, Missouri, USA
- ICCE Institute, Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Luisangely Soto Torres
- Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, Saint Louis, Missouri, USA
- ICCE Institute, Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Angela M. Schab
- Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, Saint Louis, Missouri, USA
- ICCE Institute, Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Jason D. Weber
- Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, Saint Louis, Missouri, USA
- Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, Missouri, USA
- Department of Biology, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, Missouri, USA
- ICCE Institute, Washington University School of Medicine, Saint Louis, Missouri, USA
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23
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Sun H, Li K, Liu C, Yi C. Regulation and functions of non-m 6A mRNA modifications. Nat Rev Mol Cell Biol 2023; 24:714-731. [PMID: 37369853 DOI: 10.1038/s41580-023-00622-x] [Citation(s) in RCA: 81] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2023] [Indexed: 06/29/2023]
Abstract
Nucleobase modifications are prevalent in eukaryotic mRNA and their discovery has resulted in the emergence of epitranscriptomics as a research field. The most abundant internal (non-cap) mRNA modification is N6-methyladenosine (m6A), the study of which has revolutionized our understanding of post-transcriptional gene regulation. In addition, numerous other mRNA modifications are gaining great attention because of their major roles in RNA metabolism, immunity, development and disease. In this Review, we focus on the regulation and function of non-m6A modifications in eukaryotic mRNA, including pseudouridine (Ψ), N6,2'-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), inosine, 5-methylcytidine (m5C), N4-acetylcytidine (ac4C), 2'-O-methylated nucleotide (Nm) and internal N7-methylguanosine (m7G). We highlight their regulation, distribution, stoichiometry and known roles in mRNA metabolism, such as mRNA stability, translation, splicing and export. We also discuss their biological consequences in physiological and pathological processes. In addition, we cover research techniques to further study the non-m6A mRNA modifications and discuss their potential future applications.
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Affiliation(s)
- Hanxiao Sun
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
| | - Kai Li
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Cong Liu
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
| | - Chengqi Yi
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
- Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
- Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
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24
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Morales DR, Rennie S, Uchida S. Benchmarking RNA Editing Detection Tools. BIOTECH 2023; 12:56. [PMID: 37754200 PMCID: PMC10527054 DOI: 10.3390/biotech12030056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/16/2023] [Accepted: 08/23/2023] [Indexed: 09/28/2023] Open
Abstract
RNA, like DNA and proteins, can undergo modifications. To date, over 170 RNA modifications have been identified, leading to the emergence of a new research area known as epitranscriptomics. RNA editing is the most frequent RNA modification in mammalian transcriptomes, and two types have been identified: (1) the most frequent, adenosine to inosine (A-to-I); and (2) the less frequent, cysteine to uracil (C-to-U) RNA editing. Unlike other epitranscriptomic marks, RNA editing can be readily detected from RNA sequencing (RNA-seq) data without any chemical conversions of RNA before sequencing library preparation. Furthermore, analyzing RNA editing patterns from transcriptomic data provides an additional layer of information about the epitranscriptome. As the significance of epitranscriptomics, particularly RNA editing, gains recognition in various fields of biology and medicine, there is a growing interest in detecting RNA editing sites (RES) by analyzing RNA-seq data. To cope with this increased interest, several bioinformatic tools are available. However, each tool has its advantages and disadvantages, which makes the choice of the most appropriate tool for bench scientists and clinicians difficult. Here, we have benchmarked bioinformatic tools to detect RES from RNA-seq data. We provide a comprehensive view of each tool and its performance using previously published RNA-seq data to suggest recommendations on the most appropriate for utilization in future studies.
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Affiliation(s)
| | - Sarah Rennie
- Department of Biology, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
| | - Shizuka Uchida
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, DK-2450 Copenhagen SV, Denmark
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25
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Pecori R, Ren W, Pirmoradian M, Wang X, Liu D, Berglund M, Li W, Tasakis RN, Di Giorgio S, Ye X, Li X, Arnold A, Wüst S, Schneider M, Selvasaravanan KD, Fuell Y, Stafforst T, Amini RM, Sonnevi K, Enblad G, Sander B, Wahlin BE, Wu K, Zhang H, Helm D, Binder M, Papavasiliou FN, Pan-Hammarström Q. ADAR1-mediated RNA editing promotes B cell lymphomagenesis. iScience 2023; 26:106864. [PMID: 37255666 PMCID: PMC10225930 DOI: 10.1016/j.isci.2023.106864] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 02/27/2023] [Accepted: 05/08/2023] [Indexed: 06/01/2023] Open
Abstract
Diffuse large B cell lymphoma (DLBCL) is one of the most common types of aggressive lymphoid malignancies. Here, we explore the contribution of RNA editing to DLBCL pathogenesis. We observed that DNA mutations and RNA editing events are often mutually exclusive, suggesting that tumors can modulate pathway outcomes by altering sequences at either the genomic or the transcriptomic level. RNA editing targets transcripts within known disease-driving pathways such as apoptosis, p53 and NF-κB signaling, as well as the RIG-I-like pathway. In this context, we show that ADAR1-mediated editing within MAVS transcript positively correlates with MAVS protein expression levels, associating with increased interferon/NF-κB signaling and T cell exhaustion. Finally, using targeted RNA base editing tools to restore editing within MAVS 3'UTR in ADAR1-deficient cells, we demonstrate that editing is likely to be causal to an increase in downstream signaling in the absence of activation by canonical nucleic acid receptor sensing.
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Affiliation(s)
- Riccardo Pecori
- Division of Immune Diversity (D150), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Helmholtz Institute for Translational Oncology (HI-TRON), Mainz, Germany
| | - Weicheng Ren
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Mohammad Pirmoradian
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Xianhuo Wang
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Dongbing Liu
- BGI-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Shenzhen, China
| | - Mattias Berglund
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Wei Li
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Rafail Nikolaos Tasakis
- Division of Immune Diversity (D150), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Graduate Program in Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Salvatore Di Giorgio
- Division of Immune Diversity (D150), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Xiaofei Ye
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Xiaobo Li
- BGI-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Shenzhen, China
| | - Annette Arnold
- Division of Immune Diversity (D150), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sandra Wüst
- Research Group "Dynamics of Early Viral Infection and the Innate Antiviral Response", Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Martin Schneider
- Proteomics Core Facility (W120), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Yvonne Fuell
- Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
| | - Thorsten Stafforst
- Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
| | - Rose-Marie Amini
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Kristina Sonnevi
- Hematology Unit, Department of Medicine, Huddinge, Karolinska Institutet and Medical Unit Hematology, Karolinska University Hospital, Solna, StockholmSweden
| | - Gunilla Enblad
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Birgitta Sander
- Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - Björn Engelbrekt Wahlin
- Hematology Unit, Department of Medicine, Huddinge, Karolinska Institutet and Medical Unit Hematology, Karolinska University Hospital, Solna, StockholmSweden
| | - Kui Wu
- BGI-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Shenzhen, China
| | - Huilai Zhang
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Dominic Helm
- Proteomics Core Facility (W120), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Marco Binder
- Research Group "Dynamics of Early Viral Infection and the Innate Antiviral Response", Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - F. Nina Papavasiliou
- Division of Immune Diversity (D150), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Graduate Program in Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Qiang Pan-Hammarström
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- BGI-Shenzhen, Shenzhen, China
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26
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Chen R, Li F, Guo X, Bi Y, Li C, Pan S, Coin LJM, Song J. ATTIC is an integrated approach for predicting A-to-I RNA editing sites in three species. Brief Bioinform 2023; 24:bbad170. [PMID: 37150785 PMCID: PMC10565902 DOI: 10.1093/bib/bbad170] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/12/2023] [Accepted: 04/14/2023] [Indexed: 05/09/2023] Open
Abstract
A-to-I editing is the most prevalent RNA editing event, which refers to the change of adenosine (A) bases to inosine (I) bases in double-stranded RNAs. Several studies have revealed that A-to-I editing can regulate cellular processes and is associated with various human diseases. Therefore, accurate identification of A-to-I editing sites is crucial for understanding RNA-level (i.e. transcriptional) modifications and their potential roles in molecular functions. To date, various computational approaches for A-to-I editing site identification have been developed; however, their performance is still unsatisfactory and needs further improvement. In this study, we developed a novel stacked-ensemble learning model, ATTIC (A-To-I ediTing predICtor), to accurately identify A-to-I editing sites across three species, including Homo sapiens, Mus musculus and Drosophila melanogaster. We first comprehensively evaluated 37 RNA sequence-derived features combined with 14 popular machine learning algorithms. Then, we selected the optimal base models to build a series of stacked ensemble models. The final ATTIC framework was developed based on the optimal models improved by the feature selection strategy for specific species. Extensive cross-validation and independent tests illustrate that ATTIC outperforms state-of-the-art tools for predicting A-to-I editing sites. We also developed a web server for ATTIC, which is publicly available at http://web.unimelb-bioinfortools.cloud.edu.au/ATTIC/. We anticipate that ATTIC can be utilized as a useful tool to accelerate the identification of A-to-I RNA editing events and help characterize their roles in post-transcriptional regulation.
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Affiliation(s)
- Ruyi Chen
- College of Information Engineering, Northwest A&F University, Shaanxi 712100, China
- The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, VIC 3000, Australia
| | - Fuyi Li
- College of Information Engineering, Northwest A&F University, Shaanxi 712100, China
- The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, VIC 3000, Australia
| | - Xudong Guo
- College of Information Engineering, Northwest A&F University, Shaanxi 712100, China
| | - Yue Bi
- Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, VIC 3800, Australia
| | - Chen Li
- Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, VIC 3800, Australia
| | - Shirui Pan
- School of Information and Communication Technology, Griffith University, QLD 4222, Australia
| | - Lachlan J M Coin
- The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, VIC 3000, Australia
| | - Jiangning Song
- Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, VIC 3800, Australia
- Monash Data Futures Institute, Monash University, VIC 3800, Australia
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27
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Wei L. Retrospect of the Two-Year Debate: What Fuels the Evolution of SARS-CoV-2: RNA Editing or Replication Error? Curr Microbiol 2023; 80:151. [PMID: 36976379 PMCID: PMC10044072 DOI: 10.1007/s00284-023-03279-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 03/19/2023] [Indexed: 03/29/2023]
Abstract
Mutation is one of the mechanisms of the evolutionary divergence of an organism. Under this global COVID-19 pandemic, the fast evolution of SARS-CoV-2 became one of the most worrying issues. Some researchers believed that the hosts' RNA deamination systems (APOBECs and ADARs) are the major source of mutations and have driven the evolution of SARS-CoV-2. However, apart from RNA editing, the RDRP (RNA-dependent RNA polymerase)-mediated replication errors may also contribute to the mutation of SARS-CoV-2 (just like the single-nucleotide polymorphisms/variations in eukaryotes caused by DNA replication errors). Unfortunately, it is technically unable to distinguish RNA editing and replication errors (SNPs) in this RNA virus. Here comes a fundamental question: we indeed observed the fast evolution of SARS-CoV-2, but what exactly fuels its evolution: RNA editing or replication errors? This debate lasts for 2 years. In this piece, we will retrospect the 2-year debate on RNA editing versus SNPs.
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Affiliation(s)
- Lai Wei
- College of Life Sciences, Beijing Normal University, Beijing, China.
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28
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Tyagi S, Kabade PG, Gnanapragasam N, Singh UM, Gurjar AKS, Rai A, Sinha P, Kumar A, Singh VK. Codon Usage Provide Insights into the Adaptation of Rice Genes under Stress Condition. Int J Mol Sci 2023; 24:ijms24021098. [PMID: 36674611 PMCID: PMC9861248 DOI: 10.3390/ijms24021098] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 12/14/2022] [Accepted: 12/17/2022] [Indexed: 01/09/2023] Open
Abstract
Plants experience different stresses, i.e., abiotic, or biotic, and to combat them, plants re-program the expression of growth-, metabolism-, and resistance-related genes. These genes differ in their synonymous codon usage frequency and show codon usage bias. Here, we investigated the correlation among codon usage bias, gene expression, and underlying mechanisms in rice under abiotic and biotic stress conditions. The results indicated that genes with higher expression (up- or downregulated) levels had high GC content (≥60%), a low effective number of codon usage (≤40), and exhibited strong biases towards the codons with C/G at the third nucleotide position, irrespective of stress received. TTC, ATC, and CTC were the most preferred codons, while TAC, CAC, AAC, GAC, and TGC were moderately preferred under any stress (abiotic or biotic) condition. Additionally, downregulated genes are under mutational pressure (R2 ≥ 0.5) while upregulated genes are under natural selection pressure (R2 ≤ 0.5). Based on these results, we also identified the possible target codons that can be used to design an optimized set of genes with specific codons to develop climate-resilient varieties. Conclusively, under stress, rice has a bias towards codon usage which is correlated with GC content, gene expression level, and gene length.
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Affiliation(s)
- Swati Tyagi
- International Rice Research Institute-South Asia Regional Centre (ISARC), Varanasi 221106, India
| | | | - Niranjani Gnanapragasam
- International Rice Research Institute (IRRI)-South-Asia Hub, International Crops Research Institute for the Semi-Arid Tropics, Hyderabad 502324, India
| | - Uma Maheshwar Singh
- International Rice Research Institute-South Asia Regional Centre (ISARC), Varanasi 221106, India
| | | | - Ashutosh Rai
- International Rice Research Institute-South Asia Regional Centre (ISARC), Varanasi 221106, India
| | - Pallavi Sinha
- International Rice Research Institute (IRRI)-South-Asia Hub, International Crops Research Institute for the Semi-Arid Tropics, Hyderabad 502324, India
| | - Arvind Kumar
- International Rice Research Institute-South Asia Regional Centre (ISARC), Varanasi 221106, India
| | - Vikas Kumar Singh
- International Rice Research Institute-South Asia Regional Centre (ISARC), Varanasi 221106, India
- International Rice Research Institute (IRRI)-South-Asia Hub, International Crops Research Institute for the Semi-Arid Tropics, Hyderabad 502324, India
- Correspondence:
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29
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Ruschil C, Gabernet G, Kemmerer CL, Jarboui MA, Klose F, Poli S, Ziemann U, Nahnsen S, Kowarik MC. Cladribine treatment specifically affects peripheral blood memory B cell clones and clonal expansion in multiple sclerosis patients. Front Immunol 2023; 14:1133967. [PMID: 36960053 PMCID: PMC10028280 DOI: 10.3389/fimmu.2023.1133967] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 02/13/2023] [Indexed: 03/09/2023] Open
Abstract
Introduction B cells are acknowledged as crucial players in the pathogenesis of multiple sclerosis (MS). Several disease modifying drugs including cladribine have been shown to exert differential effects on peripheral blood B cell subsets. However, little is known regarding functional changes within the peripheral B cell populations. In this study, we obtained a detailed picture of B cell repertoire changes under cladribine treatment on a combined immunoglobulin (Ig) transcriptome and proteome level. Methods We performed next-generation sequencing of Ig heavy chain (IGH) transcripts and Ig mass spectrometry in cladribine-treated patients with relapsing-remitting multiple sclerosis (n = 8) at baseline and after 6 and 12 months of treatment in order to generate Ig transcriptome and Ig peptide libraries. Ig peptides were overlapped with the corresponding IGH transcriptome in order to analyze B cell clones on a combined transcriptome and proteome level. Results The analysis of peripheral blood B cell percentages pointed towards a significant decrease of memory B cells and an increase of naive B cells following cladribine therapy. While basic IGH repertoire parameters (e.g. variable heavy chain family usage and Ig subclasses) were only slightly affected by cladribine treatment, a significantly decreased number of clones and significantly lower diversity in the memory subset was noticeable at 6 months following treatment which was sustained at 12 months. When looking at B-cell clones comprising sequences from the different time-points, clones spanning between all three time-points were significantly more frequent than clones including sequences from two time-points. Furthermore, Ig proteome analyses showed that Ig transcriptome specific peptides could mostly be equally aligned to all three time-points pointing towards a proportion of B-cell clones that are maintained during treatment. Discussion Our findings suggest that peripheral B cell related treatment effects of cladribine tablets might be exerted through a reduction of possibly disease relevant clones in the memory B cell subset without disrupting the overall clonal composition of B cells. Our results -at least partially- might explain the relatively mild side effects regarding infections and the sustained immune response after vaccinations during treatment. However, exact disease driving B cell subsets and their effects remain unknown and should be addressed in future studies.
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Affiliation(s)
- Christoph Ruschil
- Department of Neurology and Stroke, Center for Neurology, Eberhard Karls University of Tübingen, Tübingen, Germany
- Hertie-Institute for Clinical Brain Research, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Gisela Gabernet
- Quantitative Biology Center (QBiC), Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Constanze Louisa Kemmerer
- Hertie-Institute for Clinical Brain Research, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Mohamed Ali Jarboui
- Core Facility for Medical Bioanalytics (CFMB), Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Franziska Klose
- Core Facility for Medical Bioanalytics (CFMB), Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Sven Poli
- Department of Neurology and Stroke, Center for Neurology, Eberhard Karls University of Tübingen, Tübingen, Germany
- Hertie-Institute for Clinical Brain Research, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Ulf Ziemann
- Department of Neurology and Stroke, Center for Neurology, Eberhard Karls University of Tübingen, Tübingen, Germany
- Hertie-Institute for Clinical Brain Research, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Sven Nahnsen
- Quantitative Biology Center (QBiC), Eberhard Karls University of Tübingen, Tübingen, Germany
- Biomedical Data Science, Department of Computer Science, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Markus Christian Kowarik
- Department of Neurology and Stroke, Center for Neurology, Eberhard Karls University of Tübingen, Tübingen, Germany
- Hertie-Institute for Clinical Brain Research, Eberhard Karls University of Tübingen, Tübingen, Germany
- *Correspondence: Markus Christian Kowarik,
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30
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Guo Y, van der Heijden YF, Maruri F, Jiang L, Morrison R, Sterling TR. RNA editing in Mycobacterium tuberculosis. Microbiol Res 2022; 264:127174. [PMID: 36067705 PMCID: PMC11332325 DOI: 10.1016/j.micres.2022.127174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/17/2022] [Accepted: 08/19/2022] [Indexed: 11/28/2022]
Abstract
RNA editing, while studied thoroughly in humans, has been sporadically described in bacteria, and to our knowledge, has not been reported in Mycobacterium tuberculosis (Mtb). After thorough quality control and validation by repeated sequencing, by comparing sequences from RNA and DNA from high-throughput sequencing data, we report the first finding of three RNA editing events in two Mtb isolates.
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Affiliation(s)
- Yan Guo
- Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA
| | - Yuri F van der Heijden
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt Tuberculosis Center, Vanderbilt University School of Medicine, Nashville, TN, USA; The Aurum Institute, Johannesburg, South Africa
| | - Fernanda Maruri
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt Tuberculosis Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Limin Jiang
- Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA
| | | | - Timothy R Sterling
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt Tuberculosis Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
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31
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Caldwell RM, Flynn RA. Discovering glycoRNA: Traditional and Non‐Canonical Approaches to Studying RNA Modifications. Isr J Chem 2022. [DOI: 10.1002/ijch.202200059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Reese M. Caldwell
- Stem Cell Program, Boston Children's Hospital Boston 02115 Massachusetts United States
- Stem Cell and Regenerative Biology Department, Harvard University Cambridage 02138 Massachusetts United States
| | - Ryan A. Flynn
- Stem Cell Program, Boston Children's Hospital Boston 02115 Massachusetts United States
- Stem Cell and Regenerative Biology Department, Harvard University Cambridage 02138 Massachusetts United States
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32
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Fusion Gene Detection and Quantification by Asymmetric Capture Sequencing (aCAP-Seq). J Mol Diagn 2022; 24:1113-1127. [PMID: 35963522 DOI: 10.1016/j.jmoldx.2022.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/14/2022] [Accepted: 07/21/2022] [Indexed: 11/23/2022] Open
Abstract
Several fusion genes such as BCR::ABL1, FIP1L1::PDGFRA, and PML::RARA are now efficiently targeted by specific therapies in patients with leukemia. Although these therapies have significantly improved patient outcomes, leukemia relapse and progression remain clinical concerns. Most myeloid next-generation sequencing (NGS) panels do not detect or quantify these fusions. It therefore remains difficult to decipher the clonal architecture and dynamics of myeloid malignancy patients, although these factors can affect clinical decisions and provide pathophysiologic insights. An asymmetric capture sequencing strategy (aCAP-Seq) and a bioinformatics algorithm (HmnFusion) were developed to detect and quantify MBCR::ABL1, μBCR::ABL1, PML::RARA, and FIP1L1::PDGFRA fusion genes in an NGS panel targeting 41 genes. One-hundred nineteen DNA samples derived from 106 patients were analyzed by conventional methods at diagnosis or on follow-up and were sequenced with this NGS myeloid panel. The specificity and sensitivity of fusion detection by aCAP-Seq were 100% and 98.1%, respectively, with a limit of detection estimated at 0.1%. Fusion quantifications were linear from 0.1% to 50%. Breakpoint locations and sequences identified by NGS were concordant with results obtained by Sanger sequencing. Finally, this new sensitive and cost-efficient NGS method allowed integrated analysis of resistant chronic myeloid leukemia patients and thus will be of interest to elucidate the mutational landscape and clonal architecture of myeloid malignancies driven by these fusion genes at diagnosis, relapse, or progression.
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33
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Cai H, Liu X, Zheng X. RNA editing detection in SARS-CoV-2 transcriptome should be different from traditional SNV identification. J Appl Genet 2022; 63:587-594. [PMID: 35661108 PMCID: PMC9166928 DOI: 10.1007/s13353-022-00706-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/24/2022] [Accepted: 05/31/2022] [Indexed: 10/31/2022]
Affiliation(s)
- Houhao Cai
- Shandong University of Traditional Chinese Medicine, Jinan, 250000, Shandong, China
| | - Xiantao Liu
- Pulmonary and Critical Care Medicine, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Xin Zheng
- Department of Respiratory and Critical Care Medicine, The Affiliated Qingdao Hiser Hospital of Qingdao University, Qingdao, 266000, Shandong, China.
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34
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Pishesha N, Harmand TJ, Ploegh HL. A guide to antigen processing and presentation. Nat Rev Immunol 2022; 22:751-764. [PMID: 35418563 DOI: 10.1038/s41577-022-00707-2] [Citation(s) in RCA: 290] [Impact Index Per Article: 96.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2022] [Indexed: 12/13/2022]
Abstract
Antigen processing and presentation are the cornerstones of adaptive immunity. B cells cannot generate high-affinity antibodies without T cell help. CD4+ T cells, which provide such help, use antigen-specific receptors that recognize major histocompatibility complex (MHC) molecules in complex with peptide cargo. Similarly, eradication of virus-infected cells often depends on cytotoxic CD8+ T cells, which rely on the recognition of peptide-MHC complexes for their action. The two major classes of glycoproteins entrusted with antigen presentation are the MHC class I and class II molecules, which present antigenic peptides to CD8+ T cells and CD4+ T cells, respectively. This Review describes the essentials of antigen processing and presentation. These pathways are divided into six discrete steps that allow a comparison of the various means by which antigens destined for presentation are acquired and how the source proteins for these antigens are tagged for degradation, destroyed and ultimately displayed as peptides in complex with MHC molecules for T cell recognition.
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Affiliation(s)
- Novalia Pishesha
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.,Society of Fellows, Harvard University, Cambridge, MA, USA.,Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Thibault J Harmand
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Hidde L Ploegh
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
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35
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Poor evidence for host-dependent regular RNA editing in the transcriptome of SARS-CoV-2. J Appl Genet 2022; 63:413-421. [PMID: 35179717 PMCID: PMC8854479 DOI: 10.1007/s13353-022-00687-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/21/2021] [Accepted: 02/13/2022] [Indexed: 12/18/2022]
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36
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Pan Y, Li M, Huang J, Pan W, Shi T, Guo Q, Yang G, Nie X. Genome-Wide Identification and Characterization of RNA/DNA Differences Associated with Drought Response in Wheat. Int J Mol Sci 2022; 23:1405. [PMID: 35163325 PMCID: PMC8836135 DOI: 10.3390/ijms23031405] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 01/23/2022] [Accepted: 01/24/2022] [Indexed: 12/19/2022] Open
Abstract
RNA/DNA difference (RDD) is a post-transcriptional RNA modification to enrich genetic information, widely involved in regulating diverse biological processes in eukaryotes. RDDs in the wheat nuclear genome, especially those associated with drought response or tolerance, were not well studied up to now. In this study, we investigated the RDDs related to drought response based on the RNA-seq data of drought-stressed and control samples in wheat. In total, 21,782 unique RDDs were identified, of which 265 were found to be drought-induced, representing the first drought-responsive RDD landscape in the wheat nuclear genome. The drought-responsive RDDs were located in 69 genes, of which 35 were differentially expressed under drought stress. Furthermore, the effects of RNA/DNA differences were investigated, showing that they could result in changes of RNA secondary structure, miRNA-target binding as well as protein conserved domains in the RDD-containing genes. In particular, the A to C mutation in TraesCS2A02G053100 (orthology to OsRLCK) led to the loss of tae-miR9657b-5p targeting, indicating that RNA/DNA difference might mediate miRNA to regulate the drought-response process. This study reported the first drought-responsive RDDs in the wheat nuclear genome. It sheds light on the roles of RDD in drought tolerance, and may also contribute to wheat genetic improvement based on epi-transcriptome methods.
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Affiliation(s)
- Yan Pan
- State Key Laboratory of Crop Stress Biology in Arid Areas, College of Agronomy, Northwest A&F University, Yangling 712100, China; (Y.P.); (M.L.); (J.H.); (W.P.); (T.S.); (Q.G.); (G.Y.)
| | - Mengqi Li
- State Key Laboratory of Crop Stress Biology in Arid Areas, College of Agronomy, Northwest A&F University, Yangling 712100, China; (Y.P.); (M.L.); (J.H.); (W.P.); (T.S.); (Q.G.); (G.Y.)
| | - Jiaqian Huang
- State Key Laboratory of Crop Stress Biology in Arid Areas, College of Agronomy, Northwest A&F University, Yangling 712100, China; (Y.P.); (M.L.); (J.H.); (W.P.); (T.S.); (Q.G.); (G.Y.)
| | - Wenqiu Pan
- State Key Laboratory of Crop Stress Biology in Arid Areas, College of Agronomy, Northwest A&F University, Yangling 712100, China; (Y.P.); (M.L.); (J.H.); (W.P.); (T.S.); (Q.G.); (G.Y.)
| | - Tingrui Shi
- State Key Laboratory of Crop Stress Biology in Arid Areas, College of Agronomy, Northwest A&F University, Yangling 712100, China; (Y.P.); (M.L.); (J.H.); (W.P.); (T.S.); (Q.G.); (G.Y.)
| | - Qifan Guo
- State Key Laboratory of Crop Stress Biology in Arid Areas, College of Agronomy, Northwest A&F University, Yangling 712100, China; (Y.P.); (M.L.); (J.H.); (W.P.); (T.S.); (Q.G.); (G.Y.)
| | - Guang Yang
- State Key Laboratory of Crop Stress Biology in Arid Areas, College of Agronomy, Northwest A&F University, Yangling 712100, China; (Y.P.); (M.L.); (J.H.); (W.P.); (T.S.); (Q.G.); (G.Y.)
| | - Xiaojun Nie
- State Key Laboratory of Crop Stress Biology in Arid Areas, College of Agronomy, Northwest A&F University, Yangling 712100, China; (Y.P.); (M.L.); (J.H.); (W.P.); (T.S.); (Q.G.); (G.Y.)
- ICARDA-NWSUAF Joint Research Center, Yangling 712100, China
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37
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Hwang T, Kim S, Chowdhury T, Yu HJ, Kim KM, Kang H, Won JK, Park SH, Shin JH, Park CK. Genome-wide perturbations of Alu expression and Alu-associated post-transcriptional regulations distinguish oligodendroglioma from other gliomas. Commun Biol 2022; 5:62. [PMID: 35042936 PMCID: PMC8766575 DOI: 10.1038/s42003-022-03011-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 12/27/2021] [Indexed: 01/09/2023] Open
Abstract
AbstractAlu is a primate-specific repeat element in the human genome and has been increasingly appreciated as a regulatory element in many biological processes. But the appreciation of Alu has been limited in tumorigenesis, especially for brain tumor. To investigate the relevance of Alu to the gliomagenesis, we studied Alu element-associated post-transcriptional processes and the RNA expression of the element by performing RNA-seq for a total of 41 pairs of neurotypical and diverse glioma brain tissues. We find that A-to-I editing and circular RNA levels, as well as Alu RNA expression, are decreased overall in gliomas, compared to normal tissue. Interestingly, grade 2 oligodendrogliomas are least affected in A-to-I editing and circular RNA levels among gliomas, whereas they have a higher proportion of down-regulated Alu subfamilies, compared to the other gliomas. These findings collectively imply a unique pattern of Alu-associated transcriptomes in grade 2 oligodendroglioma, providing an insight to gliomagenesis from the perspective of an evolutionary genetic element.
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38
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Quiver MH, Lachance J. Adaptive eQTLs reveal the evolutionary impacts of pleiotropy and tissue-specificity while contributing to health and disease. HGG ADVANCES 2022; 3:100083. [PMID: 35047867 PMCID: PMC8756519 DOI: 10.1016/j.xhgg.2021.100083] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 12/21/2021] [Indexed: 11/24/2022] Open
Abstract
Large numbers of expression quantitative trait loci (eQTLs) have recently been identified in humans, and many of these regulatory variants have large allele frequency differences between populations. Here, we conducted genome-wide scans of selection to identify adaptive eQTLs (i.e., eQTLs with large population branch statistics). We then tested if tissue pleiotropy affects whether eQTLs are more or less likely to be adaptive and identified tissues that have been key targets of positive selection during the last 100,000 years. Top adaptive eQTL outliers include rs1043809, rs66899053, and rs2814778 (a SNP that is associated with malaria resistance). We found that effect sizes of eQTLs were negatively correlated with population branch statistics and that adaptive eQTLs affect two-thirds as many tissues as do non-adaptive eQTLs. Because the tissue breadth of an eQTL can be viewed as a measure of pleiotropy, these results imply that pleiotropy inhibits adaptation. The proportion of eQTLs that are adaptive varies by tissue, and we found that eQTLs that regulate expression in testis, thyroid, blood, or sun-exposed skin are enriched for signatures of positive selection. By contrast, eQTLs that regulate expression in the cerebrum or female-specific tissues have a relative lack of adaptive outliers. Scans of selections also reveal that many adaptive eQTLs are closely linked to disease-associated loci. Taken together, our results indicate that eQTLs have played an important role in recent human evolution.
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Affiliation(s)
- Melanie H Quiver
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Joseph Lachance
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA
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39
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Akhlaghpour H. An RNA-Based Theory of Natural Universal Computation. J Theor Biol 2021; 537:110984. [PMID: 34979104 DOI: 10.1016/j.jtbi.2021.110984] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 09/30/2021] [Accepted: 12/07/2021] [Indexed: 12/15/2022]
Abstract
Life is confronted with computation problems in a variety of domains including animal behavior, single-cell behavior, and embryonic development. Yet we currently do not know of a naturally existing biological system that is capable of universal computation, i.e., Turing-equivalent in scope. Generic finite-dimensional dynamical systems (which encompass most models of neural networks, intracellular signaling cascades, and gene regulatory networks) fall short of universal computation, but are assumed to be capable of explaining cognition and development. I present a class of models that bridge two concepts from distant fields: combinatory logic (or, equivalently, lambda calculus) and RNA molecular biology. A set of basic RNA editing rules can make it possible to compute any computable function with identical algorithmic complexity to that of Turing machines. The models do not assume extraordinarily complex molecular machinery or any processes that radically differ from what we already know to occur in cells. Distinct independent enzymes can mediate each of the rules and RNA molecules solve the problem of parenthesis matching through their secondary structure. In the most plausible of these models all of the editing rules can be implemented with merely cleavage and ligation operations at fixed positions relative to predefined motifs. This demonstrates that universal computation is well within the reach of molecular biology. It is therefore reasonable to assume that life has evolved - or possibly began with - a universal computer that yet remains to be discovered. The variety of seemingly unrelated computational problems across many scales can potentially be solved using the same RNA-based computation system. Experimental validation of this theory may immensely impact our understanding of memory, cognition, development, disease, evolution, and the early stages of life.
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Affiliation(s)
- Hessameddin Akhlaghpour
- Laboratory of Integrative Brain Function, The Rockefeller University, New York, NY, 10065, USA
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40
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Tao S, Ren Z, Yang Z, Duan S, Wan Z, Huang J, Liu C, Wei G. Effects of Different Molecular Weight Polysaccharides From Dendrobium officinale Kimura & Migo on Human Colorectal Cancer and Transcriptome Analysis of Differentially Expressed Genes. Front Pharmacol 2021; 12:704486. [PMID: 34925000 PMCID: PMC8678483 DOI: 10.3389/fphar.2021.704486] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 10/27/2021] [Indexed: 12/13/2022] Open
Abstract
We investigated the antitumor effects of four fractions of Dendrobium officinale Kimura & Migo (D. officinale) polysaccharides with different molecular weights (Mw), Astragalus membranaceus polysaccharides (APS) and Lentinus edodes polysaccharides (LNT) on colorectal cancer (CRC) using a zebrafish xenograft model. Transcriptome sequencing was performed to further explore the possible antitumor mechanisms of D. officinale polysaccharides. Fractions of D. officinale polysaccharides, LNT, and APS could significantly inhibit the growth of HT-29 cells in a zebrafish xenograft model. One fraction of D. officinale polysaccharides called DOPW-1 (Mw of 389.98 kDa) exhibited the strongest tumor inhibition. Compared with the control group, RNA-seq revealed that the DOPW-1–treated experimental group had 119 differentially expressed genes (DEGs), of which 45 had upregulated expression and 74 had downregulated expression. Analyses using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes suggested that the pathway “apoptosis-multiple species” was the most significantly enriched. Our data indicated that 1) fractions of D. officinale polysaccharides of Mw 389.98 kDa were most suitable against CRC; 2) DOPW-1 could be developed into a clinical agent against CRC; and 3) an apoptosis pathway is important for DOPW-1 to inhibit the proliferation of HT-29 cells.
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Affiliation(s)
- Shengchang Tao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Pharmacy, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, China
| | - Zhiyao Ren
- Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou, China.,NHC Key Laboratory of Male Reproduction and Genetics, Guangzhou, China.,Department of Central Laboratory, Family Planning Research Institute of Guangdong Province, Guangzhou, China
| | - Zerui Yang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shuna Duan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Shaoguan Institute of Danxia Dendrobium Officinale, Shaoguan, China
| | - Zhongxian Wan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiahui Huang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Shaoguan Institute of Danxia Dendrobium Officinale, Shaoguan, China
| | - Chenxing Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Shaoguan Institute of Danxia Dendrobium Officinale, Shaoguan, China
| | - Gang Wei
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
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41
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Ma Y, Dammer EB, Felsky D, Duong DM, Klein HU, White CC, Zhou M, Logsdon BA, McCabe C, Xu J, Wang M, Wingo TS, Lah JJ, Zhang B, Schneider J, Allen M, Wang X, Ertekin-Taner N, Seyfried NT, Levey AI, Bennett DA, De Jager PL. Atlas of RNA editing events affecting protein expression in aged and Alzheimer's disease human brain tissue. Nat Commun 2021; 12:7035. [PMID: 34857756 PMCID: PMC8640037 DOI: 10.1038/s41467-021-27204-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 11/04/2021] [Indexed: 11/09/2022] Open
Abstract
RNA editing is a feature of RNA maturation resulting in the formation of transcripts whose sequence differs from the genome template. Brain RNA editing may be altered in Alzheimer's disease (AD). Here, we analyzed data from 1,865 brain samples covering 9 brain regions from 1,074 unrelated subjects on a transcriptome-wide scale to identify inter-regional differences in RNA editing. We expand the list of known brain editing events by identifying 58,761 previously unreported events. We note that only a small proportion of these editing events are found at the protein level in our proteome-wide validation effort. We also identified the occurrence of editing events associated with AD dementia, neuropathological measures and longitudinal cognitive decline in: SYT11, MCUR1, SOD2, ORAI2, HSDL2, PFKP, and GPRC5B. Thus, we present an extended reference set of brain RNA editing events, identify a subset that are found to be expressed at the protein level, and extend the narrative of transcriptomic perturbation in AD to RNA editing.
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Affiliation(s)
- Yiyi Ma
- Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, 630 West 168th street, New York, NY, 10032, USA
| | - Eric B Dammer
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Integrated Proteomics Core Facility, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Daniel Felsky
- Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Duc M Duong
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Integrated Proteomics Core Facility, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Hans-Ulrich Klein
- Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, 630 West 168th street, New York, NY, 10032, USA
| | - Charles C White
- Cell Circuits Program, Broad Institute, 415 Main street, Cambridge, MA, 02142, USA
| | - Maotian Zhou
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Integrated Proteomics Core Facility, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | | | - Cristin McCabe
- Cell Circuits Program, Broad Institute, 415 Main street, Cambridge, MA, 02142, USA
| | - Jishu Xu
- Rush Alzheimer's Disease Center, Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, 60612, USA
| | - Minghui Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Thomas S Wingo
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - James J Lah
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Bin Zhang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Julie Schneider
- Rush Alzheimer's Disease Center, Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, 60612, USA
| | - Mariet Allen
- Mayo Clinic Florida, Department of Neuroscience, Jacksonville, FL, 32224, USA
| | - Xue Wang
- Mayo Clinic Florida, Department of Health Sciences Research, Jacksonville, FL, 32224, USA
| | - Nilüfer Ertekin-Taner
- Mayo Clinic Florida, Department of Neuroscience, Jacksonville, FL, 32224, USA
- Mayo Clinic Florida, Department of Neurology, Jacksonville, FL, 32224, USA
| | - Nicholas T Seyfried
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Integrated Proteomics Core Facility, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Allan I Levey
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - David A Bennett
- Rush Alzheimer's Disease Center, Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, 60612, USA
| | - Philip L De Jager
- Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, 630 West 168th street, New York, NY, 10032, USA.
- Cell Circuits Program, Broad Institute, 415 Main street, Cambridge, MA, 02142, USA.
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42
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Tedjasaputra TR, Hatta M, Massi MN, Natzir R, Bukhari A, Masadah R, Parewangi ML, Prihantono P, Nariswati R, Tedjasaputra V. Prediction of hereditary nonpolyposis colorectal cancer using mRNA MSH2 quantitative and the correlation with nonmodifiable factor. World J Gastrointest Pathophysiol 2021; 12:130-142. [DOI: 10.4291/wjgp.v12.i6.130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hereditary non-polyposis colon cancer is a dominantly inherited syndrome of colorectal cancer (CRC), with heightened risk for younger population. Previous studies link its susceptibility to the DNA sequence polymorphism along with Amsterdam and Bethesda criteria. However, those fail in term of applicability.
AIM To determine a clear cut-off of MSH2 gene expression for CRC heredity grouping factor. Further, the study also aims to examine the association of risk factors to the CRC heredity.
METHODS The cross-sectional study observed 71 respondents from May 2018 to December 2019 in determining the CRC hereditary status through MSH2 mRNA expression using reverse transcription-polymerase chain reaction and the disease’s risk factors. Data were analyzed through Chi-Square, Fischer exact, t-test, Mann-Whitney, and multiple logistics.
RESULTS There are significant differences of MSH2 within CRC group among tissue and blood; yet, negative for significance between groups. Through the blood gene expression fifth percentile, the hereditary CRC cut-off is 11059 fc, dividing the 40 CRC respondents to 32.5% with hereditary CRC. Significant risk factors include age, family history, and staging. Nonetheless, after multivariate control, age is just a confounder. Further, the study develops a probability equation with area under the curve 82.2%.
CONCLUSION Numerous factors have significant relations to heredity of CRC patients. However, true important factors are staging and family history, while age and others are confounders. The study also established a definite cut-off point for heredity CRC based on mRNA MSH2 expression, 11059 fc. These findings shall act as concrete foundations on further risk factors and/or genetical CRC future studies.
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Affiliation(s)
- Tjahjadi Robert Tedjasaputra
- Department of Internal Medicine, Tarakan General Hospital, Medical Faculty University of Hasanuddin, Jakarta 10720, DKI Jakarta, Indonesia
| | - Mochammad Hatta
- Department of Immunology and Biomolecular, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Muh Nasrum Massi
- Department of Microbiology, Faculty of Medicine, University of Hasanuddin, Makassar 90245, South Sulawesi, Indonesia
| | - Rosdiana Natzir
- Department of Biochemistry Meidcal Faculty, University of Hasanuddin, Makassar 90245, South Sulawesi, Indonesia
| | - Agussalim Bukhari
- Department of Nutrition, Faculty of Medicine, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Rina Masadah
- Department of Pathology Anatomy, Faculty of Medicine, Hasanuddin University, Makassar 20945, South Sulawesi, Indonesia
| | - Muh Lutfi Parewangi
- Department of Internal Medicine, Faculty of Medicine, Hasanuddin University, Makassar 20945, South Sulawesi, Indonesia
| | - Prihantono Prihantono
- Department of Surgery, Faculty of Medicine, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Rinda Nariswati
- Department of Statistic, School of Computer Science, Bina Nusantara University Jakarta, Jakarta 11530, Indonesia
| | - Vincent Tedjasaputra
- American Association for the Advancement of Science (AAAS), Science and Technology Policy Fellow, Alexandria, VA 22314, United States
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Tedjasaputra TR, Hatta M, Massi MN, Natzir R, Bukhari A, Masadah R, Parewangi ML, Prihantono P, Nariswati R, Tedjasaputra V. Prediction of hereditary nonpolyposis colorectal cancer using mRNA MSH2 quantitative and the correlation with nonmodifiable factor. World J Gastrointest Pathophysiol 2021; 12:134-146. [PMID: 34877027 PMCID: PMC8611184 DOI: 10.4291/wjgp.v12.i6.134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/13/2021] [Accepted: 10/11/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hereditary non-polyposis colon cancer is a dominantly inherited syndrome of colorectal cancer (CRC), with heightened risk for younger population. Previous studies link its susceptibility to the DNA sequence polymorphism along with Amsterdam and Bethesda criteria. However, those fail in term of applicability. AIM To determine a clear cut-off of MSH2 gene expression for CRC heredity grouping factor. Further, the study also aims to examine the association of risk factors to the CRC heredity. METHODS The cross-sectional study observed 71 respondents from May 2018 to December 2019 in determining the CRC hereditary status through MSH2 mRNA expression using reverse transcription-polymerase chain reaction and the disease's risk factors. Data were analyzed through Chi-Square, Fischer exact, t-test, Mann-Whitney, and multiple logistics. RESULTS There are significant differences of MSH2 within CRC group among tissue and blood; yet, negative for significance between groups. Through the blood gene expression fifth percentile, the hereditary CRC cut-off is 11059 fc, dividing the 40 CRC respondents to 32.5% with hereditary CRC. Significant risk factors include age, family history, and staging. Nonetheless, after multivariate control, age is just a confounder. Further, the study develops a probability equation with area under the curve 82.2%. CONCLUSION Numerous factors have significant relations to heredity of CRC patients. However, true important factors are staging and family history, while age and others are confounders. The study also established a definite cut-off point for heredity CRC based on mRNA MSH2 expression, 11059 fc. These findings shall act as concrete foundations on further risk factors and/or genetical CRC future studies.
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Affiliation(s)
- Tjahjadi Robert Tedjasaputra
- Department of Internal Medicine, Tarakan General Hospital, Medical Faculty University of Hasanuddin, Jakarta 10720, DKI Jakarta, Indonesia
| | - Mochammad Hatta
- Department of Immunology and Biomolecular, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Muh Nasrum Massi
- Department of Microbiology, Faculty of Medicine, University of Hasanuddin, Makassar 90245, South Sulawesi, Indonesia
| | - Rosdiana Natzir
- Department of Biochemistry Meidcal Faculty, University of Hasanuddin, Makassar 90245, South Sulawesi, Indonesia
| | - Agussalim Bukhari
- Department of Nutrition, Faculty of Medicine, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Rina Masadah
- Department of Pathology Anatomy, Faculty of Medicine, Hasanuddin University, Makassar 20945, South Sulawesi, Indonesia
| | - Muh Lutfi Parewangi
- Department of Internal Medicine, Faculty of Medicine, Hasanuddin University, Makassar 20945, South Sulawesi, Indonesia
| | - Prihantono Prihantono
- Department of Surgery, Faculty of Medicine, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Rinda Nariswati
- Department of Statistic, School of Computer Science, Bina Nusantara University Jakarta, Jakarta 11530, Indonesia
| | - Vincent Tedjasaputra
- American Association for the Advancement of Science (AAAS), Science and Technology Policy Fellow, Alexandria, VA 22314, United States
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Wen J, Rusch M, Brady SW, Shao Y, Edmonson MN, Shaw TI, Powers BB, Tian L, Easton J, Mullighan CG, Gruber T, Ellison D, Zhang J. The landscape of coding RNA editing events in pediatric cancer. BMC Cancer 2021; 21:1233. [PMID: 34789196 PMCID: PMC8597231 DOI: 10.1186/s12885-021-08956-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 11/02/2021] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND RNA editing leads to post-transcriptional variation in protein sequences and has important biological implications. We sought to elucidate the landscape of RNA editing events across pediatric cancers. METHODS Using RNA-Seq data mapped by a pipeline designed to minimize mapping ambiguity, we investigated RNA editing in 711 pediatric cancers from the St. Jude/Washington University Pediatric Cancer Genome Project focusing on coding variants which can potentially increase protein sequence diversity. We combined de novo detection using paired tumor DNA-RNA data with analysis of known RNA editing sites. RESULTS We identified 722 unique RNA editing sites in coding regions across pediatric cancers, 70% of which were nonsynonymous recoding variants. Nearly all editing sites represented the canonical A-to-I (n = 706) or C-to-U sites (n = 14). RNA editing was enriched in brain tumors compared to other cancers, including editing of glutamate receptors and ion channels involved in neurotransmitter signaling. RNA editing profiles of each pediatric cancer subtype resembled those of the corresponding normal tissue profiled by the Genotype-Tissue Expression (GTEx) project. CONCLUSIONS In this first comprehensive analysis of RNA editing events in pediatric cancer, we found that the RNA editing profile of each cancer subtype is similar to its normal tissue of origin. Tumor-specific RNA editing events were not identified indicating that successful immunotherapeutic targeting of RNA-edited peptides in pediatric cancer should rely on increased antigen presentation on tumor cells compared to normal but not on tumor-specific RNA editing per se.
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Affiliation(s)
- Ji Wen
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Michael Rusch
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Samuel W Brady
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Ying Shao
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Michael N Edmonson
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Timothy I Shaw
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Brent B Powers
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Liqing Tian
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - John Easton
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Charles G Mullighan
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Tanja Gruber
- Department of Pediatrics, Stanford University, Palo Alto, California, 94305, USA
| | - David Ellison
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Jinghui Zhang
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
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Owens MC, Zhang C, Liu KF. Recent technical advances in the study of nucleic acid modifications. Mol Cell 2021; 81:4116-4136. [PMID: 34480848 PMCID: PMC9109655 DOI: 10.1016/j.molcel.2021.07.036] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 07/20/2021] [Accepted: 07/28/2021] [Indexed: 12/30/2022]
Abstract
Enzyme-mediated chemical modifications of nucleic acids are indispensable regulators of gene expression. Our understanding of the biochemistry and biological significance of these modifications has largely been driven by an ever-evolving landscape of technologies that enable accurate detection, mapping, and manipulation of these marks. Here we provide a summary of recent technical advances in the study of nucleic acid modifications with a focus on techniques that allow accurate detection and mapping of these modifications. For each modification discussed (N6-methyladenosine, 5-methylcytidine, inosine, pseudouridine, and N4-acetylcytidine), we begin by introducing the "gold standard" technique for its mapping and detection, followed by a discussion of techniques developed to address any shortcomings of the gold standard. By highlighting the commonalities and differences of these techniques, we hope to provide a perspective on the current state of the field and to lay out a guideline for development of future technologies.
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Affiliation(s)
- Michael C Owens
- Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Celia Zhang
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kathy Fange Liu
- Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Tan KT, Ding LW, Wu CS, Tenen DG, Yang H. Repurposing RNA sequencing for discovery of RNA modifications in clinical cohorts. SCIENCE ADVANCES 2021; 7:eabd2605. [PMID: 34348892 PMCID: PMC8336963 DOI: 10.1126/sciadv.abd2605] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 06/14/2021] [Indexed: 05/07/2023]
Abstract
The study of RNA modifications in large clinical cohorts can reveal relationships between the epitranscriptome and human diseases, although this is especially challenging. We developed ModTect (https://github.com/ktan8/ModTect), a statistical framework to identify RNA modifications de novo by standard RNA-sequencing with deletion and mis-incorporation signals. We show that ModTect can identify both known (N 1-methyladenosine) and previously unknown types of mRNA modifications (N 2,N 2-dimethylguanosine) at nucleotide-resolution. Applying ModTect to 11,371 patient samples and 934 cell lines across 33 cancer types, we show that the epitranscriptome was dysregulated in patients across multiple cancer types and was additionally associated with cancer progression and survival outcomes. Some types of RNA modification were also more disrupted than others in patients with cancer. Moreover, RNA modifications contribute to multiple types of RNA-DNA sequence differences, which unexpectedly escape detection by Sanger sequencing. ModTect can thus be used to discover associations between RNA modifications and clinical outcomes in patient cohorts.
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Affiliation(s)
- Kar-Tong Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Biological and Biomedical Sciences Program, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA
- Department of Computer Science, School of Computing, National University of Singapore, Singapore, Singapore
| | - Ling-Wen Ding
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Chan-Shuo Wu
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Daniel G Tenen
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
- Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA
| | - Henry Yang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Light D, Haas R, Yazbak M, Elfand T, Blau T, Lamm AT. RESIC: A Tool for Comprehensive Adenosine to Inosine RNA Editing Site Identification and Classification. Front Genet 2021; 12:686851. [PMID: 34367244 PMCID: PMC8343188 DOI: 10.3389/fgene.2021.686851] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 06/07/2021] [Indexed: 11/25/2022] Open
Abstract
Adenosine to inosine (A-to-I) RNA editing, the most prevalent type of RNA editing in metazoans, is carried out by adenosine deaminases (ADARs) in double-stranded RNA regions. Several computational approaches have been recently developed to identify A-to-I RNA editing sites from sequencing data, each addressing a particular issue. Here, we present RNA Editing Sites Identification and Classification (RESIC), an efficient pipeline that combines several approaches for the detection and classification of RNA editing sites. The pipeline can be used for all organisms and can use any number of RNA-sequencing datasets as input. RESIC provides (1) the detection of editing sites in both repetitive and non-repetitive genomic regions; (2) the identification of hyper-edited regions; and (3) optional exclusion of polymorphism sites to increase reliability, based on DNA, and ADAR-mutant RNA sequencing datasets, or SNP databases. We demonstrate the utility of RESIC by applying it to human, successfully overlapping and extending the list of known putative editing sites. We further tested changes in the patterns of A-to-I RNA editing, and RNA abundance of ADAR enzymes, following SARS-CoV-2 infection in human cell lines. Our results suggest that upon SARS-CoV-2 infection, compared to mock, the number of hyper editing sites is increased, and in agreement, the activity of ADAR1, which catalyzes hyper-editing, is enhanced. These results imply the involvement of A-to-I RNA editing in conceiving the unpredicted phenotype of COVID-19 disease. RESIC code is open-source and is easily extendable.
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Affiliation(s)
- Dean Light
- Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel
| | - Roni Haas
- Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel
| | - Mahmoud Yazbak
- Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel
| | - Tal Elfand
- Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel
| | - Tal Blau
- Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel
| | - Ayelet T Lamm
- Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel
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Yévenes M, Núñez-Acuña G, Gallardo-Escárate C, Gajardo G. Adaptive Differences in Gene Expression in Farm-Impacted Seedbeds of the Native Blue Mussel Mytilus chilensis. Front Genet 2021; 12:666539. [PMID: 34093658 PMCID: PMC8174845 DOI: 10.3389/fgene.2021.666539] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 04/23/2021] [Indexed: 01/02/2023] Open
Abstract
The study of adaptive population differences is relevant for evolutionary biology, as it evidences the power of selective local forces relative to gene flow in maintaining adaptive phenotypes and their underlying genetic determinants. However, human-mediated hybridization through habitat translocations, a common and recurrent aquaculture practice where hybrids could eventually replace local genotypes, risk populations' ability to cope with perturbations. The endemic marine mussel Mytilus chilensis supports a booming farming industry in the inner sea of Chiloé Island, southern Chile, which entirely relies on artificially collected seeds from natural beds that are translocated to ecologically different fattening centers. A matter of concern is how farm-impacted seedbeds will potentially cope with environmental shifts and anthropogenic perturbations. This study provides the first de novo transcriptome of M. chilensis; assembled from tissue samples of mantles and gills of individuals collected in ecologically different farm-impacted seedbeds, Cochamó (41°S) and Yaldad (43°S). Both locations and tissue samples differentially expressed transcripts (DETs) in candidate adaptive genes controlling multiple fitness traits, involved with metabolism, genetic and environmental information processing, and cellular processes. From 189,743 consensus contigs assembled: 1,716 (Bonferroni p value ≤ 0.05) were DETs detected in different tissues of samples from different locations, 210 of them (fold change ≥ | 100|) in the same tissue of samples from a different location, and 665 (fold change ≥ | 4|) regardless of the tissue in samples from a different location. Site-specific DETs in Cochamó (169) and Yaldad (150) in candidate genes controlling tolerance to temperature and salinity shifts, and biomineralization exhibit a high number of nucleotide genetic variants with regular occurrence (frequency > 99%). This novel M. chilensis transcriptome should help assessing and monitoring the impact of translocations in wild and farm-impacted mussel beds in Chiloé Island. At the same time, it would help designing effective managing practices for conservation, and translocation traceability.
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Affiliation(s)
- Marco Yévenes
- Programa de Doctorado en Ciencias, Mención Conservación y Manejo de Recursos Naturales, Universidad de Los Lagos, Osorno, Chile
- Laboratorio de Genética, Acuicultura & Biodiversidad, Departamento de Ciencias Biológicas y Biodiversidad, Universidad de Los Lagos, Osorno, Chile
| | - Gustavo Núñez-Acuña
- Laboratorio de Biotecnología y Genómica Acuícola, Centro Interdisciplinario para la Investigación en Acuicultura, Universidad de Concepción, Concepción, Chile
| | - Cristian Gallardo-Escárate
- Laboratorio de Biotecnología y Genómica Acuícola, Centro Interdisciplinario para la Investigación en Acuicultura, Universidad de Concepción, Concepción, Chile
| | - Gonzalo Gajardo
- Laboratorio de Genética, Acuicultura & Biodiversidad, Departamento de Ciencias Biológicas y Biodiversidad, Universidad de Los Lagos, Osorno, Chile
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Torsin LI, Petrescu GED, Sabo AA, Chen B, Brehar FM, Dragomir MP, Calin GA. Editing and Chemical Modifications on Non-Coding RNAs in Cancer: A New Tale with Clinical Significance. Int J Mol Sci 2021; 22:ijms22020581. [PMID: 33430133 PMCID: PMC7827606 DOI: 10.3390/ijms22020581] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/29/2020] [Accepted: 12/30/2020] [Indexed: 12/11/2022] Open
Abstract
Currently, for seemingly every type of cancer, dysregulated levels of non-coding RNAs (ncRNAs) are reported and non-coding transcripts are expected to be the next class of diagnostic and therapeutic tools in oncology. Recently, alterations to the ncRNAs transcriptome have emerged as a novel hallmark of cancer. Historically, ncRNAs were characterized mainly as regulators and little attention was paid to the mechanisms that regulate them. The role of modifications, which can control the function of ncRNAs post-transcriptionally, only recently began to emerge. Typically, these modifications can be divided into reversible (i.e., chemical modifications: m5C, hm5C, m6A, m1A, and pseudouridine) and non-reversible (i.e., editing: ADAR dependent, APOBEC dependent and ADAR/APOBEC independent). The first research papers showed that levels of these modifications are altered in cancer and can be part of the tumorigenic process. Hence, the aim of this review paper is to describe the most common regulatory modifications (editing and chemical modifications) of the traditionally considered “non-functional” ncRNAs (i.e., microRNAs, long non-coding RNAs and circular RNAs) in the context of malignant disease. We consider that only by understanding this extra regulatory layer it is possible to translate the knowledge about ncRNAs and their modifications into clinical practice.
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Affiliation(s)
- Ligia I. Torsin
- Department of Anesthesiology and Critical Care, Elias Clinical Emergency Hospital, 011461 Bucharest, Romania;
| | - George E. D. Petrescu
- Department of Neurosurgery, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (G.E.D.P.); (F.M.B.)
- Department of Neurosurgery, Bagdasar-Arseni Clinical Emergency Hospital, 041915 Bucharest, Romania
| | - Alexandru A. Sabo
- Zentrum für Kinder, Jugend und Frauenmedizin, Pediatrics 2 (General and Special Pediatrics), Klinikum Stuttgart, Olgahospital, 70174 Stuttgart, Germany;
| | - Baoqing Chen
- State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China;
- Guangdong Esophageal Cancer Research Institute, Guangzhou 510060, China
| | - Felix M. Brehar
- Department of Neurosurgery, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (G.E.D.P.); (F.M.B.)
- Department of Neurosurgery, Bagdasar-Arseni Clinical Emergency Hospital, 041915 Bucharest, Romania
| | - Mihnea P. Dragomir
- Institute of Pathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
- Correspondence: or (M.P.D.); (G.A.C.); Tel.: +40-254-219-493 (M.P.D.); +1-713-792-5461 (G.A.C.)
| | - George A. Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
- Correspondence: or (M.P.D.); (G.A.C.); Tel.: +40-254-219-493 (M.P.D.); +1-713-792-5461 (G.A.C.)
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Abstract
RNA editing of adenosines to inosines contributes to a wide range of biological processes by regulating gene expression post-transcriptionally. To understand the effect, accurate mapping of inosines is necessary. The most conventional method to identify an editing site is to compare the cDNA sequence with its corresponding genomic sequence. However, this method has a high false discovery rate because guanosine signals, due to experimental errors or noise in the obtained sequences, contaminate genuine inosine signals detected as guanosine. To ensure high accuracy, we developed the Inosine Chemical Erasing (ICE) method to accurately and biochemically identify inosines in RNA strands utilizing inosine cyanoethylation and reverse transcription-PCR. Furthermore, we applied this technique to next-generation sequencing technology, called ICE-seq, to conduct an unbiased genome-wide screening of A-to-I editing sites in the transcriptome.
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