4.6 Article

Transcriptome-Wide Analysis of UTRs in Non-Small Cell Lung Cancer Reveals Cancer-Related Genes with SNV-Induced Changes on RNA Secondary Structure and miRNA Target Sites

期刊

PLOS ONE
卷 9, 期 1, 页码 -

出版社

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0082699

关键词

-

资金

  1. Danish Center for Scientific Computing (DCSC, DeiC)
  2. Danish Council for Strategic Research (Programme Commission on Strategic Growth Technologies)
  3. Danish Council for Independent Research (Technology and Production Sciences)

向作者/读者索取更多资源

Traditional mutation assessment methods generally focus on predicting disruptive changes in protein-coding regions rather than non-coding regulatory regions like untranslated regions (UTRs) of mRNAs. The UTRs, however, are known to have many sequence and structural motifs that can regulate translational and transcriptional efficiency and stability of mRNAs through interaction with RNA-binding proteins and other non-coding RNAs like microRNAs (miRNAs). In a recent study, transcriptomes of tumor cells harboring mutant and wild-type KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) genes in patients with non-small cell lung cancer (NSCLC) have been sequenced to identify single nucleotide variations (SNVs). About 40% of the total SNVs (73,717) identified were mapped to UTRs, but omitted in the previous analysis. To meet this obvious demand for analysis of the UTRs, we designed a comprehensive pipeline to predict the effect of SNVs on two major regulatory elements, secondary structure and miRNA target sites. Out of 29,290 SNVs in 6462 genes, we predict 472 SNVs (in 408 genes) affecting local RNA secondary structure, 490 SNVs (in 447 genes) affecting miRNA target sites and 48 that do both. Together these disruptive SNVs were present in 803 different genes, out of which 188 (23.4%) were previously known to be cancer-associated. Notably, this ratio is significantly higher (one-sided Fisher's exact test p-value = 0.032) than the ratio (20.8%) of known cancer-associated genes (n = 1347) in our initial data set (n = 6462). Network analysis shows that the genes harboring disruptive SNVs were involved in molecular mechanisms of cancer, and the signaling pathways of LPS-stimulated MAPK, IL-6, iNOS, EIF2 and mTOR. In conclusion, we have found hundreds of SNVs which are highly disruptive with respect to changes in the secondary structure and miRNA target sites within UTRs. These changes hold the potential to alter the expression of known cancer genes or genes linked to cancer-associated pathways.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.6
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

Article Biochemistry & Molecular Biology

Does rapid sequence divergence preclude RNA structure conservation in vertebrates?

Stefan E. Seemann, Aashiq H. Mirza, Claus H. Bang-Berthelsen, Christian Garde, Mikkel Christensen-Dalsgaard, Christopher T. Workman, Flemming Pociot, Niels Tommerup, Jan Gorodkin, Walter L. Ruzzo

Summary: The accelerated evolution of RNA structures in vertebrates, though rare, does not preclude the conservation of their functions, as shown in the study.

NUCLEIC ACIDS RESEARCH (2022)

Article Cell Biology

PTBP1 promotes hematopoietic stem cell maintenance and red blood cell development by ensuring sufficient availability of ribosomal constituents

Matilda Rehn, Anne Wenzel, Anne-Katrine Frank, Mikkel Bruhn Schuster, Sachin Pundhir, Nanna Jorgensen, Kristoffer Vitting-Seerup, Ying Ge, Johan Jendholm, Magali Michaut, Erwin M. Schoof, Tanja Lyholm Jensen, Nicolas Rapin, Russell T. Sapio, Kasper Langebjerg Andersen, Anders H. Lund, Michele Solimena, Martin Holzenberger, Dimitri G. Pestov, Bo Torben Porse

Summary: Ribosomopathies are a range of disorders that affect protein synthesis and primarily impact hematopoietic stem cells and erythroid development. This study demonstrates that the deletion of poly-pyrimidine-tract-binding protein 1 (PTBP1) in the hematopoietic compartment leads to a condition resembling ribosomopathy. The loss of PTBP1 results in reduced HSC self-renewal, erythroid differentiation, and protein synthesis, along with defects in splicing and ribosome biogenesis.

CELL REPORTS (2022)

Article Biochemical Research Methods

CRISPRon/off: CRISPR/Cas9 on- and off-target gRNA design

Christian Anthon, Giulia Ilaria Corsi, Jan Gorodkin

Summary: The effectiveness of CRISPR/Cas9-mediated genome editing experiments relies on the careful selection of guide RNA (gRNA) for target recognition and cleavage activation. This study presents a user-friendly webserver that incorporates both on- and off-target prediction tools, CRISPRon and CRISPRoff, to facilitate gRNA selection.

BIOINFORMATICS (2022)

Article Genetics & Heredity

The Bacillaceae-1 RNA motif comprises two distinct classes

Enrique Gonzalez-Tortuero, Christian Anthon, Jakob H. Havgaard, Adrian S. Geissler, Anne Breuner, Carsten Hjort, Jan Gorodkin, Stefan E. Seemann

Summary: Non-coding RNAs play important regulatory roles in bacteria, but many predicted non-coding RNAs lack functional associations. The study finds that Bacillaceae-1 RNA motif is conserved in non-pathogenic strains of the genus Bacillus, with different structural and genomic context characteristics. Furthermore, it is observed that the motif has different expression patterns and structural features depending on its location upstream of the ribosomal RNA cluster or between coding genes.
Article Biochemistry & Molecular Biology

Active enhancers strengthen insulation by RNA-mediated CTCF binding at chromatin domain boundaries

Zubairul Islam, Bharath Saravanan, Kaivalya Walavalkar, Umer Farooq, Anurag Kumar Singh, Radhakrishnan Sabarinathan, Jitendra Thakur, Awadhesh Pandit, Steven Henikoff, Dimple Notani

Summary: Vertebrate genomes are divided into chromatin domains called topologically associating domains (TADs), which are typically bound by pairs of CTCF binding sites. Transcription at domain boundaries is correlated with better insulation, and this study shows that boundary-associated RNAs aid in the recruitment and clustering of CTCF at TAD borders. These boundary-associated RNAs enhance TAD insulation, enhancer-promoter interactions, and gene expression within the TAD.

GENOME RESEARCH (2023)

Article Biochemistry & Molecular Biology

Cross-species high-resolution transcriptome profiling suggests biomarkers and therapeutic targets for ulcerative colitis

Reza Yarani, Oana Palasca, Nadezhda T. Doncheva, Christian Anthon, Bartosz Pilecki, Cecilie A. S. Svane, Aashiq H. Mirza, Thomas Litman, Uffe Holmskov, Claus H. Bang-Berthelsen, Mogens Vilien, Lars J. Jensen, Jan Gorodkin, Flemming Pociot

Summary: This study identified common conserved pathological UC-related gene expression signatures between humans and mice by comparing gene expression data. These signatures can be used as treatment targets or biomarker candidates. Less known genes with importance in disease pathogenesis were identified and validated in different samples. The findings contribute to disease phenotyping, treatment decisions, drug discovery, and clinical trial design.

FRONTIERS IN MOLECULAR BIOSCIENCES (2023)

Article Oncology

Prognostic association of immunoproteasome expression in solid tumours is governed by the immediate immune environment

Rahul Kumar, Bhavya Dhaka, Sarthak Sahoo, Mohit Kumar Jolly, Radhakrishnan Sabarinathan

Summary: Induction of immunoproteasome expression in tumour cells can improve antigen presentation and immune response. However, the association between IP expression and overall prognosis and response to ICB therapy varies among different solid tumours and is influenced by immune cell infiltration patterns.

MOLECULAR ONCOLOGY (2023)

Article Neurosciences

The transcriptomic landscape of neurons carrying PSEN1 mutations reveals changes in extracellular matrix components and non-coding gene expression

Giulia I. Corsi, Veerendra P. Gadekar, Henriette Haukedal, Nadezhda T. Doncheva, Christian Anthon, Sheetal Ambardar, Dasaradhi Palakodeti, Poul Hyttel, Kristine Freude, Stefan E. Seemann, Jan Gorodkin

Summary: Alzheimer's disease (AD) is a progressive and irreversible brain disorder caused by complex factors. This study investigates the gene expression changes in neurons with fAD mutations in the PSEN1 gene using hiPSCs. The analysis reveals significant alterations in genes related to extracellular matrix, calcium homeostasis, mitochondrial oxidative stress, and circular RNA. These findings contribute to a better understanding of the cellular mechanisms in AD neurons.

NEUROBIOLOGY OF DISEASE (2023)

Article Neurosciences

Golgi fragmentation - One of the earliest organelle phenotypes in Alzheimer's disease neurons

Henriette Haukedal, Giulia I. Corsi, Veerendra P. Gadekar, Nadezhda T. Doncheva, Shekhar Kedia, Noortje de Haan, Abinaya Chandrasekaran, Pia Jensen, Pernille Schionning, Sarah Vallin, Frederik Ravnkilde Marlet, Anna Poon, Carlota Pires, Fawzi Khoder Agha, Hans H. Wandall, Susanna Cirera, Anja Hviid Simonsen, Troels Tolstrup Nielsen, Jorgen Erik Nielsen, Poul Hyttel, Ravi Muddashetty, Blanca I. Aldana, Jan Gorodkin, Deepak Nair, Morten Meyer, Martin Rossel Larsen, Kristine Freude

Summary: Alzheimer's disease is a common cause of dementia with no cure. This study investigated specific disease phenotypes in glutamatergic forebrain neurons and identified Golgi fragmentation as one of the earliest AD phenotypes. The study also found that genetic variants in SORL1 could aggravate Golgi fragmentation and glycosylation changes.

FRONTIERS IN NEUROSCIENCE (2023)

Article Agriculture, Dairy & Animal Science

RNA-Seq Study on the Longissimus thoracis Muscle of Italian Large White Pigs Fed Extruded Linseed with or without Antioxidants and Polyphenols

Jacopo Vegni, Ying Sun, Stefan E. Seemann, Martina Zappaterra, Roberta Davoli, Stefania Dall'Olio, Jan Gorodkin, Paolo Zambonelli

Summary: Dietary intake of omega-3 polyunsaturated fatty acids and antioxidants in humans has anti-inflammatory and antioxidant effects. However, the use of omega-3 polyunsaturated fatty acids in pig diet has been less studied. This study aimed to investigate gene expression differences in the muscle tissue of pigs fed with different diets. The results showed that adding omega-3 polyunsaturated fatty acids and antioxidants to the diet improved the lipid composition and anti-inflammatory potential of the muscle tissue.

ANIMALS (2023)

Article Immunology

Alteration of microglial metabolism and inflammatory profile contributes to neurotoxicity in a hiPSC-derived microglia model of frontotemporal dementia 3

Henriette Haukedal, Signe Syshoj Lorenzen, Emil Winther Westi, Giulia I. Corsi, Veerendra P. Gadekar, Amanda McQuade, Hayk Davtyan, Nadezhda T. Doncheva, Benjamin Schmid, Abinaya Chandrasekaran, Stefan E. Seemann, Susanna Cirera, Mathew Blurton-Jones, Morten Meyer, Jan Gorodkin, Blanca I. Aldana, Kristine Freude

Summary: FTD is a common form of early-onset dementia with no current treatment options. FTD3 is a rare subtype of the disease caused by a mutation in the CHMP2B gene. This study explores the role of glial cells, specifically microglia, in FTD3 pathogenesis and identifies different inflammatory profiles and behaviors based on the CHMP2B mutation status.

BRAIN BEHAVIOR AND IMMUNITY (2023)

Article Biotechnology & Applied Microbiology

Systematic analysis and characterization of long non-coding RNA genes in inflammatory bowel disease

Rania Velissari, Mirolyuba Ilieva, James Dao, Henry E. Miller, Jens Hedelund Madsen, Jan Gorodkin, Masanori Aikawa, Hideshi Ishii, Shizuka Uchida

Summary: The cases of inflammatory bowel disease (IBD) are increasing rapidly worldwide. High-throughput techniques are being used to understand the molecular changes associated with IBD, including genetic mutations, microbiome environments, transcriptome, and proteome. However, non-coding RNAs (ncRNAs), particularly long non-coding RNAs (lncRNAs), have been largely unexplored in IBD research. This study re-analyzed RNA-seq data and conducted loss-of-function experiments to study the expression profiles and functional relevance of lncRNAs in IBD. A web database, IBDB, was also developed to facilitate further research on lncRNAs in IBD.

BRIEFINGS IN FUNCTIONAL GENOMICS (2023)

Article Multidisciplinary Sciences

TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression

Elizabeth Heyes, Anna S. Wilhelmson, Anne Wenzel, Gabriele Manhart, Thomas Eder, Mikkel B. Schuster, Edwin Rzepa, Sachin Pundhir, Teresa DAltri, Anne-Katrine Frank, Coline Gentil, Jakob Woessmann, Erwin M. Schoof, Manja Meggendorfer, Jurg Schwaller, Torsten Haferlach, Florian Grebien, Bo T. Porse

Summary: The myeloid transcription factor CEBPA is frequently mutated in acute myeloid leukemia, and its co-mutation with GATA2 and TET2 is common. This study reveals the molecular mechanisms of these co-mutations, showing that CEBPA(NT) enhances GATA2 expression while loss of TET2 increases Gata2 promoter methylation in CEBPA(DM) AML, leading to balanced GATA2 levels. Demethylating treatment can restore Gata2 levels and prolong disease latency in CEBPA-TET2 co-mutated AML.

NATURE COMMUNICATIONS (2023)

Letter Biochemical Research Methods

Letter to the editor: Testing on external independent datasets is necessary to corroborate machine learning model improvement

Giulia Ilaria Corsi, Christian Anthon, Jan Gorodkin

BIOINFORMATICS (2023)

Article Oncology

Cis-regulatory effect of HPV integration is constrained by host chromatin architecture in cervical cancers

Anurag Kumar Singh, Kaivalya Walavalkar, Daniele Tavernari, Giovanni Ciriello, Dimple Notani, Radhakrishnan Sabarinathan

Summary: The integration of human papillomavirus (HPV) into the host genome affects the expression of adjacent genes, and this study reveals that the effects differ depending on the chromatin state at the integration site. The integration of HPV leads to the upregulation of nearby genes within the same topologically associating domains (TADs), but does not affect genes in adjacent TADs. Recurrent HPV integration in specific TADs results in the overexpression of oncogenes.

MOLECULAR ONCOLOGY (2023)

暂无数据