Comprehensive functional profiling of long non-coding RNAs through a novel pan-cancer integration approach and modular analysis of their protein-coding gene association networks

Eukaryotic genomes express numerous long intergenic non-coding RNAs (lincRNAs) that do not overlap any coding genes. Some lincRNAs function in various aspects of gene regulation, but it is not clear in general to what extent lincRNAs contribute to the information flow from genotype to phenotype. To explore this question, we systematically analysed cellular roles of lincRNAs in Schizosaccharomyces pombe. Using seamless CRISPR/Cas9-based genome editing, we deleted 141 lincRNA genes to broadly phenotype these mutants, together with 238 diverse coding-gene mutants for functional context. We applied high-throughput colony-based assays to determine mutant growth and viability in benign conditions and in response to 145 different nutrient, drug, and stress conditions. These analyses uncovered phenotypes for 47.5% of the lincRNAs and 96% of the protein-coding genes. For 110 lincRNA mutants, we also performed high-throughput microscopy and flow cytometry assays, linking 37% of these lincRNAs with cell-size and/or cell-cycle control. With all assays combined, we detected phenotypes for 84 (59.6%) of all lincRNA deletion mutants tested. For complementary functional inference, we analysed colony growth of strains ectopically overexpressing 113 lincRNA genes under 47 different conditions. Of these overexpression strains, 102 (90.3%) showed altered growth under certain conditions. Clustering analyses provided further functional clues and relationships for some of the lincRNAs. These rich phenomics datasets associate lincRNA mutants with hundreds of phenotypes, indicating that most of the lincRNAs analysed exert cellular functions in specific environmental or physiological contexts. This study provides groundwork to further dissect the roles of these lincRNAs in the relevant conditions.

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Comprehensive functional profiling of long non-coding RNAs through a novel pan-cancer integration approach and modular analysis of their protein-coding gene association networks

10.1101/254722 ◽

2018 ◽

Author(s):

Kevin Walters ◽

Radmir Sarsenov ◽

Wen Siong Too ◽

Roseanna K. Hare ◽

Ian C. Paterson ◽

...

Keyword(s):

Genomic Sequence ◽

Therapeutic Potential ◽

Tumour Progression ◽

Expression Profiles ◽

Critical Role ◽

Multiple Cancer ◽

Protein Coding ◽

Cancer Types ◽

Non Coding Rnas ◽

Pan Cancer

AbstractLong non-coding RNAs (lncRNAs) are emerging as crucial regulators of cellular processes in diseases such as cancer, although the functions of most remain poorly understood. To address this, here we apply a novel strategy to integrate gene expression profiles across 32 cancer types, and cluster human lncRNAs based on their pan-cancer protein-coding gene associations. By doing so, we derive 16 lncRNA modules whose unique properties allow simultaneous inference of function, disease specificity and regulation for over 800 lncRNAs. Remarkably, modules could be grouped into just four functional themes: transcription regulation, immunological, extracellular, and neurological, with module generation frequently driven by lncRNA tissue specificity. Notably, three modules associated with the extracellular matrix represented potential networks of lncRNAs regulating key events in tumour progression. These included a tumour-specific signature of 33 lncRNAs that may play a role in inducing epithelialmesenchymal transition through modulation of TGFβ signalling, and two stromal-specific modules comprising 26 lncRNAs linked to a tumour suppressive microenvironment, and 12 lncRNAs related to cancer-associated fibroblasts. At least one member of the 12-lncRNA signature was experimentally supported by siRNA knockdown, which resulted in attenuated differentiation of quiescent fibroblasts to a cancer-associated phenotype. Overall, the study provides a unique pan-cancer perspective on the lncRNA functional landscape, acting as a global source of novel hypotheses on lncRNA contribution to tumour progression.Author SummaryThe established view of protein production is that genomic DNA is transcribed into RNA, which is then translated into protein. Proteins play a critical role in shaping the function of each individual cell in the human body yet they represent less than 2% of human genomic sequence whilst up to 90% of the genome is transcribed. To explain this disparity, the existence of thousands of long non-coding RNAs (lncRNAs) has emerged that do not encode proteins but perform function as an RNA molecule. Most lncRNAs have yet to be assigned a specific biological role, so to address this we apply a novel computational approach to characterise the function of >800 lncRNAs through consistent association with protein coding genes across multiple cancer types. By doing so, we discover 16 “modules” of closely related lncRNAs that share broad functional themes, the most compelling of which consists of 12 lncRNAs that could regulate activation of specific cells neighbouring the tumour, leading to accelerated tumour progression and invasion. Overall, the study provides the most robust view of the lncRNA-protein coding gene landscape to date, adding to growing evidence that lncRNAs are key regulators of cancer, and have therapeutic potential comparable to proteins.

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Genome-wide identification of the essential protein-coding genes and long non-coding RNAs for human pan-cancer

Bioinformatics ◽

10.1093/bioinformatics/btz230 ◽

2019 ◽

Vol 35 (21) ◽

pp. 4344-4349 ◽

Cited By ~ 5

Author(s):

Yuwei Zhang ◽

Yang Tao ◽

Huihui Ji ◽

Wei Li ◽

Xingli Guo ◽

...

Keyword(s):

Network Analysis ◽

Regulatory Network ◽

Essential Genes ◽

Supplementary Information ◽

Published Data ◽

Biological Processes ◽

Protein Coding ◽

Protein Coding Genes ◽

Non Coding Rnas ◽

Pan Cancer

Abstract Motivation Genome-scale CRISPR/Cas9 system has been a democratized gene editing technique and widely used to investigate gene functions in some biological processes and diseases especially cancers. Aiming to characterize gene aberrations and assess their effects on cancer, we designed a pipeline to identify the essential genes for pan-cancer. Methods CRISPR screening data were used to identify the essential genes that were collected from published data and integrated by Robust Rank Aggregation algorithm. Then, hypergeometrics test and random walks with restart (RWR) were used to predict additional essential genes on broader scale. Finally, the expression status and potential roles of these genes were explored based on TCGA portal and regulatory network analysis. Results We collected 926 samples from 10 CRISPR-based screening studies involving 33 different types of cancer to identify cancer-essential genes, which consists of 799 protein-coding genes (PCGs) and 97 long non-coding RNAs (lncRNAs). Then, we constructed a ‘bi-colored’ network with both PCGs and lncRNAs and applied it to predict additional essential genes including 495 PCGs and 280 lncRNAs on a broader scale using hypergeometrics test and RWR. After obtaining all essential genes, we further investigated their potential roles in cancer and found that essential genes have higher and more stable expression levels, and are associated with multiple cancer-associated biological processes and survival time. The regulatory network analysis detected two intriguing modules of essential genes participating in the regulation of cell cycle and ribosome biogenesis in cancer. Availability and implementation Supplementary information Supplementary data are available at Bioinformatics online.

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Pan-Cancer Analysis Reveals Common and Specific Relationships between Intragenic miRNAs and Their Host Genes

Biomedicines ◽

10.3390/biomedicines9091263 ◽

2021 ◽

Vol 9 (9) ◽

pp. 1263

Author(s):

Baohong Liu ◽

Yu Shyr ◽

Qi Liu

Keyword(s):

Mirna Biogenesis ◽

Comprehensive Investigation ◽

Protein Coding ◽

Protein Coding Genes ◽

Specific Cancer ◽

Precursor Mirnas ◽

Cancer Types ◽

Non Coding Rnas ◽

Pan Cancer ◽

Host Genes

MicroRNAs (miRNAs) are small endogenous non-coding RNAs that play important roles in regulating gene expression. Most miRNAs are located within or close to genes (host). miRNAs and their host genes have either coordinated or independent transcription. We performed a comprehensive investigation on co-transcriptional patterns of miRNAs and host genes based on 4707 patients across 21 cancer types. We found that only 11.6% of miRNA-host pairs were co-transcribed consistently and strongly across cancer types. Most miRNA-host pairs showed a strong coexpression only in some specific cancer types, demonstrating a high heterogenous pattern. For two particular types of intergenic miRNAs, readthrough and divergent miRNAs, readthrough miRNAs showed higher coexpression with their host genes than divergent ones. miRNAs located within non-coding genes had tighter co-transcription with their hosts than those located within protein-coding genes, especially exonic and junction miRNAs. A few precursor miRNAs changed their dominate form between 5′ and 3′ strands in different cancer types, including miR-486, miR-99b, let-7e, miR-125a, let-7g, miR-339, miR-26a, miR-16, and miR-218, whereas only two miRNAs with multiple host genes switched their co-transcriptional partner in different cancer types (miR-219a-1 with SLC39A7/HSD17B8 and miR-3615 with RAB37/SLC9A3R1). miRNAs generated from distinct precursors (such as miR-125b from miR-125b-1 or miR-125b-2) were more likely to have cancer-dependent main contributors. miRNAs and hosts were less co-expressed in KIRC than other cancer types, possibly due to its frequent VHL mutations. Our findings shed new light on miRNA biogenesis and cancer diagnosis and treatments.

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Investigation of long non-coding RNAs as regulatory players of grapevine response to powdery and downy mildew infection

BMC Plant Biology ◽

10.1186/s12870-021-03059-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Garima Bhatia ◽

Santosh K. Upadhyay ◽

Anuradha Upadhyay ◽

Kashmir Singh

Keyword(s):

Downy Mildew ◽

Plasmopara Viticola ◽

Defense Responses ◽

Protein Coding ◽

Functional Roles ◽

Real Time Quantitative Pcr ◽

Transcriptional Reprogramming ◽

Sequencing Technologies ◽

Non Coding Rnas ◽

Fungal Phytopathogens

Abstract Background Long non-coding RNAs (lncRNAs) are regulatory transcripts of length > 200 nt. Owing to the rapidly progressing RNA-sequencing technologies, lncRNAs are emerging as considerable nodes in the plant antifungal defense networks. Therefore, we investigated their role in Vitis vinifera (grapevine) in response to obligate biotrophic fungal phytopathogens, Erysiphe necator (powdery mildew, PM) and Plasmopara viticola (downy mildew, DM), which impose huge agro-economic burden on grape-growers worldwide. Results Using computational approach based on RNA-seq data, 71 PM- and 83 DM-responsive V. vinifera lncRNAs were identified and comprehensively examined for their putative functional roles in plant defense response. V. vinifera protein coding sequences (CDS) were also profiled based on expression levels, and 1037 PM-responsive and 670 DM-responsive CDS were identified. Next, co-expression analysis-based functional annotation revealed their association with gene ontology (GO) terms for ‘response to stress’, ‘response to biotic stimulus’, ‘immune system process’, etc. Further investigation based on analysis of domains, enzyme classification, pathways enrichment, transcription factors (TFs), interactions with microRNAs (miRNAs), and real-time quantitative PCR of lncRNAs and co-expressing CDS pairs suggested their involvement in modulation of basal and specific defense responses such as: Ca2+-dependent signaling, cell wall reinforcement, reactive oxygen species metabolism, pathogenesis related proteins accumulation, phytohormonal signal transduction, and secondary metabolism. Conclusions Overall, the identified lncRNAs provide insights into the underlying intricacy of grapevine transcriptional reprogramming/post-transcriptional regulation to delay or seize the living cell-dependent pathogen growth. Therefore, in addition to defense-responsive genes such as TFs, the identified lncRNAs can be further examined and leveraged to candidates for biotechnological improvement/breeding to enhance fungal stress resistance in this susceptible fruit crop of economic and nutritional importance.

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Pan-cancer Feature Selection and Classification Reveals Important Long Non-coding RNAs

2020 IEEE International Conference on Bioinformatics and Biomedicine (BIBM) ◽

10.1109/bibm49941.2020.9313332 ◽

2020 ◽

Author(s):

Abdullah Al Mamun ◽

Wenrui Duan ◽

Ananda Mohan Mondal

Keyword(s):

Feature Selection ◽

Non Coding Rnas ◽

Pan Cancer

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Non-Coding RNAs as Prognostic Markers for Endometrial Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22063151 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3151 ◽

Cited By ~ 2

Author(s):

Roberto Piergentili ◽

Simona Zaami ◽

Anna Franca Cavaliere ◽

Fabrizio Signore ◽

Giovanni Scambia ◽

...

Keyword(s):

Endometrial Cancer ◽

Prognostic Markers ◽

Classification Systems ◽

Prognostic Role ◽

Protein Coding ◽

Pathological Characteristics ◽

Epigenetic Events ◽

Cancer Types ◽

Non Coding Rnas

Endometrial cancer (EC) has been classified over the years, for prognostic and therapeutic purposes. In recent years, classification systems have been emerging not only based on EC clinical and pathological characteristics but also on its genetic and epigenetic features. Noncoding RNAs (ncRNAs) are emerging as promising markers in several cancer types, including EC, for which their prognostic value is currently under investigation and will likely integrate the present prognostic tools based on protein coding genes. This review aims to underline the importance of the genetic and epigenetic events in the EC tumorigenesis, by expounding upon the prognostic role of ncRNAs.

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RNA sequencing of transcriptomes in human brain regions: protein-coding and non-coding RNAs, isoforms and alleles

BMC Genomics ◽

10.1186/s12864-015-2207-8 ◽

2015 ◽

Vol 16 (1) ◽

Cited By ~ 14

Author(s):

Amy Webb ◽

Audrey C. Papp ◽

Amanda Curtis ◽

Leslie C. Newman ◽

Maciej Pietrzak ◽

...

Keyword(s):

Human Brain ◽

Rna Sequencing ◽

Brain Regions ◽

Protein Coding ◽

Non Coding Rnas

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CALINCA—A Novel Pipeline for the Identification of lncRNAs in Podocyte Disease

Cells ◽

10.3390/cells10030692 ◽

2021 ◽

Vol 10 (3) ◽

pp. 692

Author(s):

Sweta Talyan ◽

Samantha Filipów ◽

Michael Ignarski ◽

Magdalena Smieszek ◽

He Chen ◽

...

Keyword(s):

Cell Biology ◽

Mammalian Cells ◽

De Novo ◽

Depth Information ◽

Gene Products ◽

Classical Analysis ◽

Protein Coding ◽

Bioinformatic Pipeline ◽

Non Coding Rnas ◽

Filtration Unit

Diseases of the renal filtration unit—the glomerulus—are the most common cause of chronic kidney disease. Podocytes are the pivotal cell type for the function of this filter and focal-segmental glomerulosclerosis (FSGS) is a classic example of a podocytopathy leading to proteinuria and glomerular scarring. Currently, no targeted treatment of FSGS is available. This lack of therapeutic strategies is explained by a limited understanding of the defects in podocyte cell biology leading to FSGS. To date, most studies in the field have focused on protein-coding genes and their gene products. However, more than 80% of all transcripts produced by mammalian cells are actually non-coding. Here, long non-coding RNAs (lncRNAs) are a relatively novel class of transcripts and have not been systematically studied in FSGS to date. The appropriate tools to facilitate lncRNA research for the renal scientific community are urgently required due to a row of challenges compared to classical analysis pipelines optimized for coding RNA expression analysis. Here, we present the bioinformatic pipeline CALINCA as a solution for this problem. CALINCA automatically analyzes datasets from murine FSGS models and quantifies both annotated and de novo assembled lncRNAs. In addition, the tool provides in-depth information on podocyte specificity of these lncRNAs, as well as evolutionary conservation and expression in human datasets making this pipeline a crucial basis to lncRNA studies in FSGS.

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393 DECONVOLUTING THE COMPLEXITY OF LONG NON-CODING RNAS AND ESOPHAGEAL CARCINOMA FOR POTENTIAL CLINICAL IMPLICATIONS

Diseases of the Esophagus ◽

10.1093/dote/doab052.393 ◽

2021 ◽

Vol 34 (Supplement_1) ◽

Author(s):

Siyuan Luan ◽

Yushang Yang ◽

Shouyue Zhang ◽

Xiaoxi Zeng ◽

Xin Xiao ◽

...

Keyword(s):

Esophageal Carcinoma ◽

Rapid Development ◽

Direct Interaction ◽

Clinical Applications ◽

Regulatory Mechanisms ◽

Protein Coding ◽

Functional Roles ◽

Cancer Hallmarks ◽

Clinical Scenarios ◽

Non Coding Rnas

Abstract Long non-coding RNAs (lncRNAs), a type of transcriptional products with more than 200 nucleotides in length, have been less characterized compared to protein-coding RNAs so far. However, it is increasingly evident that lncRNAs are key players involved in multiple genetic and epigenetic activities during the carcinogenesis of neoplastic diseases. Currently, accumulating data have pointed out the close connection between lncRNAs and esophageal carcinoma (EC), shedding light on further unravelling the complexity of lncRNAs and EC. Methods In this review, we thoroughly collect the evidence regarding original studies on EC-related lncRNAs by searching in MEDLINE/PubMed, Embase and WOS/SCI. We especially focus on summarizing EC-related lncRNAs based upon more updated evidence, and further discuss their different features from various perspectives, including regulatory mechanisms, functional roles in cancer hallmarks, as well as potential diagnostic and therapeutic applications, which would together reveal the complexity of lncRNAs and EC for potential clinical applications. Results We discuss over thirty EC-related lncRNAs in total, most of which function as oncogenes that promote cancer development, while the others function as tumor suppressors. Regulatory mechanisms included sponging miRNAs, direct interaction with proteins, and exosome visicle-based intercellular communication. Based upon these modes of actions, lncRNAs play multiple roles in cancer hallmarks such as uncontrolled cell growth, evasion of programmed cell death, invasion and metastasis. Moreover, lncRNAs packaged in exosomes have unique potency to serve as diagnostic biomarkers; some lncRNAs show great potential to predict patients' chemical resistance and may be crucial targets to improve chemoradiotherapy and targeted therapy. Conclusion Over the past few years, the research of EC-related lncRNAs maintain obviously rapid development, yet further exploration of exact mechanisms and clinical applications that lncRNAs can offer need to be done. Indeed, LncRNAs hold the promise of being applied in multiple clinical scenarios, especially early diagnosis of EC, improvement of sensitivity to chemotherapy/radiotherapy, and development of small-molecule targeted drugs.

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