LncRNA2Function: a comprehensive resource for functional investigation of human lncRNAs based on RNA-seq data
- Qinghua Jiang†1,
- Rui Ma†2,
- Jixuan Wang3,
- Xiaoliang Wu3,
- Shuilin Jin4,
- Jiajie Peng2,
- Renjie Tan2,
- Tianjiao Zhang2,
- Yu Li1 and
- Yadong Wang2Email author
© Jiang et al.; licensee BioMed Central Ltd. 2015
Published: 29 January 2015
The GENCODE project has collected over 10,000 human long non-coding RNA (lncRNA) genes. However, the vast majority of them remain to be functionally characterized. Computational investigation of potential functions of human lncRNA genes is helpful to guide further experimental studies on lncRNAs.
In this study, based on expression correlation between lncRNAs and protein-coding genes across 19 human normal tissues, we used the hypergeometric test to functionally annotate a single lncRNA or a set of lncRNAs with significantly enriched functional terms among the protein-coding genes that are significantly co-expressed with the lncRNA(s). The functional terms include all nodes in the Gene Ontology (GO) and 4,380 human biological pathways collected from 12 pathway databases. We successfully mapped 9,625 human lncRNA genes to GO terms and biological pathways, and then developed the first ontology-driven user-friendly web interface named lncRNA2Function, which enables researchers to browse the lncRNAs associated with a specific functional term, the functional terms associated with a specific lncRNA, or to assign functional terms to a set of human lncRNA genes, such as a cluster of co-expressed lncRNAs. The lncRNA2Function is freely available at http://mlg.hit.edu.cn/lncrna2function.
The LncRNA2Function is an important resource for further investigating the functions of a single human lncRNA, or functionally annotating a set of human lncRNAs of interest.
Thousands of human long non-coding RNAs (lncRNAs) have been identified and emerging studies have revealed that lncRNAs play important roles in a wide range of biological processes [1, 2] and diseases [3, 4]. However, functions of most human lncRNAs are still elusive. Functions of a lncRNA may be determined by loss- and gain-of-function biological experiments [5, 6]. However, this is not straightforward since it is difficult to knock down a lncRNA expressed as multiple isoforms. Alternatively, computational exploration of human lncRNA functions is helpful to guide further studies on lncRNAs.
Currently, computational investigation of lncRNA functions is still at its early development stage, since it is a considerable challenge due to the characteristics of lncRNAs, e.g., many lncRNA gene sequences are not conserved and do not contain conserved sequence motifs , which makes it difficult to infer potential functions of lncRNAs based on their sequences alone. In addition, few available molecular interaction data of new identified lncRNAs also hamper the lncRNA functional annotations [8, 9].
Since genes with similar expression patterns across multiple conditions may share similar functions  or be involved in related biological pathways , identifying protein-coding genes that are co-expressed with lncRNAs may help to assign functions to the lncRNAs. By analyzing lncRNA-mRNA co-expression pattern, Guttman et al. identified several sets of mouse lncRNAs associated with protein-coding gene sets of distinct GO functional categories . In addition, two recent studies separately constructed a mouse co-expressed lncRNA-mRNA network using mouse microarray data and assigned functions to 340 and 1,625 mouse lncRNAs [13, 14].
Despite accumulating insights into the mouse lncRNA functions, more than 10,000 human lncRNAs remain to be functionally characterized. Firstly, given a single human lncRNA gene, it needs to be established whether it executes crucial biological functions. Secondly, given a set of human lncRNA genes such as differential lncRNAs between cancer and normal samples, it is an important downstream task to identify significantly enriched function terms. Thirdly, given an important functional term such as a Wnt signalling pathway, how to know which lncRNAs may be involved in the pathway.
Here, based on the expression correlation between lncRNAs and protein-coding genes inferred from RNA-seq data of 19 human normal tissues, we functionally annotated 9,625 human lncRNAs with significantly enriched functional terms among the co-expressed protein-coding genes, and developed a user-friendly web interface for the lncRNA community to obtain the lncRNAs associated with a specific functional term, the functional terms associated with a specific lncRNA, or to assign functions to a set of human lncRNAs of interest.
We downloaded: (1) genomic coordinates of all human lncRNA genes and protein-coding genes from the GENCODE V15 , (2) paired-end RNA-Seq data of 19 human normal tissues from the Human Body Map 2 project (ArrayExpress accession no. E-MTAB-513) and another study (GEO accession no. GSE30554), (3) GO assignments for the proteins of the human UniProtKB Complete Proteome from the website of the Gene Ontology Project , (4) 4,380 human biological pathways from the ConsensusPathDB database which integrated 12 pathway databases .
Workflow of LncRNA2Function
GO and pathway enrichment analysis of human lncRNAs
Herein, N is the number of all protein-coding genes in human genome, M is the number of protein-coding genes that were annotated in the functional term T, n is the number of protein-coding genes that were significantly co-expressed with the lncRNA, and m is the number of protein-coding genes that were both significantly co-expressed with the lncRNA and annotated in the functional term T.
For each GO term, protein-coding genes directly belong to it as well as those belong to any of its offspring terms are all considered as its annotated genes. Since the statistical analysis is not appropriate to problems with small sample size, those GO and pathway terms with less than 5 annotated protein-coding genes and those lncRNAs with less than 5 co-expressed protein-coding genes were excluded form the enrichment analysis.
Given a set of human lncRNA genes of interest, LncRNA2Function first identify a set of protein-coding genes, each of which are significantly co-expressed with one or more of the given lncRNAs across 19 human normal tissues. Then, the set of lncRNAs are functionally annotated with the enriched GO and pathway terms among the set of co-expressed protein-coding genes. If researchers input a large number of lncRNAs, the LncRNA2Function may obtain thousands of co-expressed protein-coding genes, some of which are co-expressed with only one of the lncRNAs. To improve the accuracy of functional assignments to the set of lncRNAs, users can select the protein-coding genes that are co-expressed with at least K lncRNAs (the K can be assigned based on the size of the set of lncRNAs. The default K is 1).
There are two commonly used methods for controlling false discovery rate (FDR), the Benjamini-Yekutieli (BY) method  and the Benjamini-Hochberg (BH) method . The former is suitable for positively related multiple hypothesis tests whereas the later is suitable for independent multiple hypothesis tests . Since the hierarchical GO terms are often dependent, we chose the BY method to correct the P-values from the GO enrichment analysis, and the BH method to correct the P-values from the pathway enrichment analysis. The significant cut-off of corrected P-value was set as 0.05.
Results and discussion
Functional annotations of a single human lncRNA
We obtained 5,232,299 significantly co-expressed pairs between 9,625 human lncRNA genes and 10,919 protein-coding genes. Each of the 9,625 lncRNAs was functionally annotated with significantly enriched GO terms and biological pathways among its co-expressed protein-coding genes. Consequently, we obtained 614,174 associations between 5,735 lncRNA genes and 3,890 GO terms, and 240,050 associations between 6,062 lncRNAs and 3,034 biological pathways. To understand the major functions of lncRNAs, we ranked GO biological processes and biological pathways according to the number of lncRNAs associated with each of them. Among the top ranked 200 GO biological processes and pathways, we found that lncRNAs play roles in many important biological processes, including defense response to bacterium, DNA packaging, meiosis, developmental process, metabolic process, cell cycle process, cell adhesion, cell differentiation, Jak-STAT signaling pathway and PI3K-Akt signaling pathway. A part of the enriched functions of lncRNAs have been validated by published studies [23–26].
Due to the lack of a large gold standard dataset of known human lncRNA functions, five well-studied lncRNAs were used as the examples to show the usefulness of LncRNA2Function.
Case study 1: HOTAIR
The HOTAIR is a well-studied lncRNA. Rinn et al. found that the HOTAIR interacts with the Polycomb repressive complex 2 (PRC2) to modify chromatin and repress transcription of the HOX genes, which regulate development . Niinuma et al. revealed that overexpression of HOTAIR was strongly associated with high-risk grade and metastasis among gastrointestinal stromal tumors (GIST) specimens, and knockdown of HOTAIR suppressed GIST cell invasiveness . In addition, Gupta et al. demonstrated that the lncRNA HOTAIR is increased in expression in primary breast tumors and metastases, and enforced expression of HOTAIR in epithelial cancer cells leaded to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit breast cancer invasiveness .
The top 20 biological processes assigned to the development-regulating HOTAIR by LncRNA2Function.
Anatomical structure morphogenesis
Embryonic skeletal system development
Anatomical structure development
Skeletal system development
Multicellular organismal development
Skeletal system morphogenesis
Multicellular organismal process
Single-multicellular organism process
Extracellular matrix organization
Extracellular structure organization
Embryonic skeletal system morphogenesis
Single-organism developmental process
Chordate embryonic development
Embryo development ending in birth or egg hatching
The metastasis-associated HOTAIR was annotated with metastasis-related GO and pathway terms by LncRNA2Function.
Positive regulation of cell-cell adhesion
Beta1 integrin cell surface interactions
Extracellular matrix organization
Beta3 integrin cell surface interactions
Syndecan-1-mediated signaling events
Integrin cell surface interactions
Integrins in angiogenesis
Integrin cell surface interactions
PI3K-Akt signaling pathway
Cell surface interactions at the vascular wall
Signaling by PDGF
NCAM signaling for neurite out-growth
Platelet Adhesion to exposed collagen
VEGFR3 signaling in lymphatic endothelium
TGF-beta signaling pathway
Wnt signaling network
Degradation of the extracellular matrix
Activation of Matrix Metalloproteinases
Alpha4 beta1 integrin signaling events
Case study 2: HCP5
The lncRNA HCP5 was found to be associated with AIDS [29–31]. Rodriguez-Novoa et al. analyzed a total of 245 HIV patients and found a good correlation between HLA-B*5701 and HCP5 (negative and positive predictive values of 100% and 93%, respectively). Colombo et al. analyzed that 1,103 singles infected with human immunodeficiency virus (HIV) and concluded that HCP5 genotyping could serve as a simple screening tool for ABC-HSR, particularly in settings where sequence-based HLA typing is not available.
The top 20 biological processes assigned to the AIDS-related lncRNA HCP5 by LncRNA2Function.
Immune system process
Regulation of immune system process
Regulation of immune response
Response to stimulus
Regulation of response to stimulus
Positive regulation of immune system process
Response to stress
Positive regulation of immune response
Cellular response to stimulus
Innate immune response
Positive regulation of response to stimulus
T cell activation
Single organism signaling
Immune response-regulating signaling pathway
The top 20 pathways assigned to AIDS-related lncRNA HCP5 by our LncRNA2Function.
Natural killer cell mediated cytotoxicity
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
Adaptive Immune System
Chemokine signaling pathway
Generation of second messenger molecules
TCR signaling in naive CD4+ T cells
TCR signaling in naive CD8+ T cells
IL12-mediated signaling events
Cytokine-cytokine receptor interaction
Innate Immune System
Hematopoietic cell lineage
T cell receptor signaling pathway
Cell surface interactions at the vascular wall
Cell surface interactions at the vascular wall
Class A/1 (Rhodopsin-like receptors)
Fc-epsilon receptor I signaling in mast cells
Case study 3: HULC
The lncRNA HULC is highly upregulated in liver cancer and plays an important role in tumorigenesis . Depletion of HULC resulted in a significant deregulation of several genes involved in liver cancer , and colorectal carcinomas that metastasize to the livers but not to lymph nodes experience an up-regulation of HULC in all the samples tested (n = 8), with a strong-to-moderate expression in six out of eight .
Top 20 pathways enriched in protein-coding genes that are co-expressed with the liver-related lncRNA HULC.
Complement and coagulation cascades
Androgen and estrogen biosynthesis and metabolism
Drug metabolism - cytochrome P450
Metabolism of xenobiotics by cytochrome P450
Metabolism of amino acids and derivatives
Complement and Coagulation Cascades
Phase 1 - Functionalization of compounds
Drug metabolism - other enzymes
Case study 4: H19
H19 is an important lncRNA that play roles in the infertility  and multiple cancers such as breast cancer [36, 37], cervical cancer , liver cancer [39, 40] and bladder cancer . For example, Korucuoglu et al. revealed that H19 expression was lower in the infertility group as compared to the control group (4-fold change, P < 0.0001), and Lottin et al. showed that over-expression of H19 transcript is associated with cells exhibiting higher tumorigenic phenotypes and promotes tumor progression.
We applied the LncRNA2Function to the lncRNA H19 and found that it was annotated with 6 GO biological processes and 31 biological pathways. The GO terms includes female pregnancy (GO: 0007565), estrogen biosynthetic process (GO:0006703), growth hormone receptor signaling pathway (GO:0060396), cellular response to growth hormone stimulus (GO:0071378) and JAK-STAT cascade involved in growth hormone signaling pathway (GO:0060397), which suggest that H19 may play roles in infertility or breast cancer by participating in these biological processes. In addition, the cancer-related lncRNA H19 was correctly annotated with many important caner pathways, such as PI3K-Akt signaling pathway, GPCR signaling-G alpha s Epac and ERK pathway, Nuclear signaling by ERBB4 pathway, Akt signaling pathway and JAK-STAT-Core cancer pathway. These results suggest that our LncRNA2Function correctly recall the known functions of H19.
Case study 5: PCA3
The lncRNA prostate cancer antigen 3 (PCA3) is a highly specific biomarker upregulated and plays crucial roles in prostate cancer (PCa) [42–45]. Clarke et al. found that up-regulation of two new PCA3 isoforms in PCa tissues improves discrimination between PCa and benign prostatic hyperplasia (BPH). In 2012, the US Food and Drug Administration approved the use of the lncRNA PCA3 for the detection of prostate cancer.
To test whether our LncRNA2Function can annotate the PCA3 with prostate-related functions, we applied the LncRNA2Function to the PCA3. LncRNA2Function first identified 77 protein-coding genes that are co-expressed with the PCA3 and then annotated it with only one pathway named 'Regulation of Androgen receptor activity' (corrected P-value: 0.020385). This pathway has 62 genes, which includes 4 protein-coding genes that are co-expressed with the PCA3. These four genes are HOXB13, KLK3, KLK2 and SPDEF that have been validated to be useful in the diagnosis and monitoring of prostatic carcinoma and be suitable target for developing specific cancer therapies. Consequently, lncRNA2Function can correctly predict the functions of PCA3 by its co-expressed protein-coding genes.
Functional annotation for a set of human lncRNAs
High-throughput genomic technologies like lncRNA microarray and RNA-Seq usually generate hundreds of candidate lncRNA genes of interest, such as a cluster of co-expressed lncRNA genes across multiple conditions or a set of differentially expressed lncRNAs between cancer and normal samples. To manually map each lncRNA to functional terms is by far a simple task. Therefore, how to identify significantly enriched functions among the set of lncRNAs is an important downstream task for interpreting high-throughput experimental data.
As a proof-of-concept, a set of liver-specific lncRNAs and a set of heart-specific lncRNAs inferred from RNA-Seq data of 19 human normal tissues were used as examples to show the functionality of our lncRNA2Function system in annotating a set of lncRNAs of interest, respectively. As expected, lncRNA2Function correctly assigned the functional terms to the two distinct sets of lncRNAs. Users can test these two sets or their own lncRNA sets at our 'LncRNA set analyzer' web interface http://mlg.hit.edu.cn/lncrna2function/lncrna_enrich.jsp.
Web interface of LncRNA2Function
Thousands of human lncRNAs have been identified in recent several years, while the vast majority of the lncRNAs remain to be functionally characterized. In this study, we functionally annotate 9,625 human lncRNAs with the enriched functions among the protein-coding genes that are co-expressed with each lncRNA. Furthermore, we developed a web interface, which facilitates researchers to search the functions of a specific lncRNA or the lncRNAs associated with a given functional term, or annotate functionally a set of human lncRNAs of interest. The lncRNA2Function will become an important tool for investigating functions of human lncRNAs.
The Natural Science Foundation of China (NSFC) [61102149, 61173085], Fundamental Research Funds for the Central Universities [HIT NSRIF. 2010057, HIT BRETIII.201219] and the China National 863 High-Tech Program (2012AA02A602, 2012AA020404 and 2012AA02A601). Funding for open access publication: NSFC 
This article has been published as part of BMC Genomics Volume 16 Supplement 3, 2015: Selected articles from the 10th International Symposium on Bioinformatics Research and Applications (ISBRA-14): Genomics. The full contents of the supplement are available online at http://www.biomedcentral.com/bmcgenomics/supplements/16/S3.
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