LncRNA ontology: inferring lncRNA functions based on chromatin states and expression patterns

Accumulating evidences suggest that long non-coding RNAs (lncRNAs) perform important functions. Genome-wide chromatin-states area rich source of information about cellular state, yielding insights beyond what is typically obtained by transcriptome profiling. We propose an integrative method for genome-wide functional predictions of lncRNAs by combining chromatin states data with gene expression patterns. We first validated the method using protein-coding genes with known function annotations. Our validation results indicated that our integrative method performs better than co-expression analysis, and is accurate across different conditions. Next, by applying the integrative model genome-wide, we predicted the probable functions for more than 97% of human lncRNAs. The putative functions inferred by our method match with previously annotated by the targets of lncRNAs. Moreover, the linkage from the cellular processes influenced by cancer-associated lncRNAs to the cancer hallmarks provided a “lncRNA point-of-view” on tumor biology. Our approach provides a functional annotation of the lncRNAs, which we developed into a web-based application, LncRNA Ontology, to provide visualization, analysis, and downloading of lncRNA putative functions.

[1]  J. Rinn,et al.  Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression , 2009, Proceedings of the National Academy of Sciences.

[2]  J. Hou,et al.  Development and prospective multicenter evaluation of the long noncoding RNA MALAT-1 as a diagnostic urinary biomarker for prostate cancer , 2014, Oncotarget.

[3]  W. Bickmore,et al.  Chromatin decondensation and nuclear reorganization of the HoxB locus upon induction of transcription. , 2004, Genes & development.

[4]  Lei Han,et al.  Long non-coding RNA HOTAIR promotes glioblastoma cell cycle progression in an EZH2 dependent manner , 2014, Oncotarget.

[5]  Tao Ye,et al.  seqMINER: an integrated ChIP-seq data interpretation platform , 2010, Nucleic acids research.

[6]  Sergio Capaccioli,et al.  A pathophysiological view of the long non-coding RNA world , 2014, Oncotarget.

[7]  Jonathan D. Wren,et al.  A global meta-analysis of microarray expression data to predict unknown gene functions and estimate the literature-data divide , 2009, Bioinform..

[8]  B. Linggi,et al.  Translating the histone code into leukemia , 2005, Journal of cellular biochemistry.

[9]  Kevin Struhl,et al.  Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity. , 2003, Molecular cell.

[10]  S. Rombauts,et al.  Analysis of RNA-Seq data with TopHat and Cufflinks for genome-wide expression analysis of jasmonate-treated plants and plant cultures. , 2013, Methods in molecular biology.

[11]  Jennifer A. Mitchell,et al.  Enhancer identification in mouse embryonic stem cells using integrative modeling of chromatin and genomic features , 2012, BMC Genomics.

[12]  Kevin Y. Yip,et al.  A statistical framework for modeling gene expression using chromatin features and application to modENCODE datasets , 2011, Genome Biology.

[13]  C. Allis,et al.  Translating the Histone Code , 2001, Science.

[14]  P. Fraser,et al.  Long Noncoding RNAs Xist in Three Dimensions , 2013, Science.

[15]  Howard Y. Chang,et al.  Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions. , 2011, Molecular cell.

[16]  Xiaoke Ma,et al.  Long non-coding RNAs function annotation: a global prediction method based on bi-colored networks , 2012, Nucleic acids research.

[17]  J. Rinn,et al.  Ab initio reconstruction of transcriptomes of pluripotent and lineage committed cells reveals gene structures of thousands of lincRNAs , 2010, Nature Biotechnology.

[18]  S. Diederichs,et al.  Gutschner T , Diederichs S . The hallmarks of cancer : a long non-coding RNA point of view . RNA Biol 9 : 703-719 , 2012 .

[19]  Xing Chen,et al.  LncRNADisease: a database for long-non-coding RNA-associated diseases , 2012, Nucleic Acids Res..

[20]  Shuli Kang,et al.  Large-scale prediction of long non-coding RNA functions in a coding–non-coding gene co-expression network , 2011, Nucleic acids research.

[21]  K. Hua,et al.  The long non-coding RNA HOTAIR promotes the proliferation of serous ovarian cancer cells through the regulation of cell cycle arrest and apoptosis. , 2015, Experimental cell research.

[22]  Cole Trapnell,et al.  Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. , 2011, Genes & development.

[23]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[24]  S. Sengupta,et al.  Genome-wide analysis reveals distinct patterns of epigenetic features in long non-coding RNA loci , 2012, Nucleic acids research.

[25]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[26]  M. Latronico,et al.  Long Noncoding RNA: a New Player of Heart Failure? , 2013, Journal of Cardiovascular Translational Research.

[27]  B. Snel,et al.  Predicting gene function by conserved co-expression. , 2003, Trends in genetics : TIG.

[28]  Brian T. Lee,et al.  The UCSC Genome Browser database: 2015 update , 2014, Nucleic Acids Res..

[29]  David G. Knowles,et al.  The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression , 2012, Genome research.

[30]  R. Sharan,et al.  Network-based prediction of protein function , 2007, Molecular systems biology.

[31]  S. Dhanasekaran,et al.  The landscape of long noncoding RNAs in the human transcriptome , 2015, Nature Genetics.

[32]  Wolfgang Huber,et al.  Combinatorial effects of four histone modifications in transcription and differentiation. , 2008, Genomics.

[33]  Feng Luo,et al.  Constructing gene co-expression networks and predicting functions of unknown genes by random matrix theory , 2007, BMC Bioinformatics.

[34]  A. Quinlan.  BEDTools: The Swiss‐Army Tool for Genome Feature Analysis , 2014, Current protocols in bioinformatics.

[35]  Daniel W. A. Buchan,et al.  A large-scale evaluation of computational protein function prediction , 2013, Nature Methods.

[36]  R. Qin,et al.  Long non-coding RNA MEG3 inhibits the proliferation of cervical carcinoma cells through the induction of cell cycle arrest and apoptosis. , 2013, Neoplasma.

[37]  Howard Y. Chang,et al.  Genome regulation by long noncoding RNAs. , 2012, Annual review of biochemistry.

[38]  Manolis Kellis,et al.  Discovery and Characterization of Chromatin States for Systematic Annotation of the Human Genome , 2011, RECOMB.

[39]  Timothy J. Durham,et al.  "Systematic" , 1966, Comput. J..

[40]  Jian Chen,et al.  Long non-coding RNA HOTAIR is a powerful predictor of metastasis and poor prognosis and is associated with epithelial-mesenchymal transition in colon cancer. , 2014, Oncology reports.

[41]  R. Guigó,et al.  Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs , 2014, European heart journal.

[42]  A. Hochberg,et al.  The H19 Non-Coding RNA Is Essential for Human Tumor Growth , 2007, PloS one.

[43]  Qingshan Chang,et al.  Mdig de-represses H19 large intergenic non-coding RNA (lincRNA) by down-regulating H3K9me3 and heterochromatin , 2013, Oncotarget.

[44]  Hongbo Liu,et al.  Long non-coding RNA identification over mouse brain development by integrative modeling of chromatin and genomic features , 2013, Nucleic acids research.

[45]  Yadong Wang,et al.  LncRNA2Target: a database for differentially expressed genes after lncRNA knockdown or overexpression , 2014, Nucleic Acids Res..

[46]  Li Teng,et al.  4DGenome: a comprehensive database of chromatin interactions. , 2015, Bioinformatics.

[47]  Marcel E. Dinger,et al.  lncRNAdb v2.0: expanding the reference database for functional long noncoding RNAs , 2014, Nucleic Acids Res..

[48]  James B. Brown,et al.  Modeling gene expression using chromatin features in various cellular contexts , 2012, Genome Biology.

[49]  H. Sültmann,et al.  Long noncoding RNA: "LNCs" to cancer. , 2014, European urology.

[50]  William A. Rennie,et al.  CLIP-based prediction of mammalian microRNA binding sites , 2013, Nucleic acids research.

[51]  Jianping Lu,et al.  Genome-wide DNA methylome analysis reveals epigenetically dysregulated non-coding RNAs in human breast cancer , 2015, Scientific Reports.

[52]  Hui Zhou,et al.  starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein–RNA interaction networks from large-scale CLIP-Seq data , 2013, Nucleic Acids Res..

[53]  Junyi Wang,et al.  LncTar: a tool for predicting the RNA targets of long noncoding RNAs , 2015, Briefings Bioinform..

[54]  Xuefei Shi,et al.  Long non-coding RNAs: a new frontier in the study of human diseases. , 2013, Cancer letters.

[55]  Shiping Liu,et al.  The sequence, structure and evolutionary features of HOTAIR in mammals , 2011, BMC Evolutionary Biology.

[56]  Dustin E. Schones,et al.  Chromatin poises miRNA- and protein-coding genes for expression. , 2009, Genome research.

[57]  Cole Trapnell,et al.  TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions , 2013, Genome Biology.

[58]  S. Ning,et al.  A novel reannotation strategy for dissecting DNA methylation patterns of human long intergenic non-coding RNAs in cancers , 2014, Nucleic acids research.

[59]  Timothy J. Durham,et al.  Systematic analysis of chromatin state dynamics in nine human cell types , 2011, Nature.

[60]  Min Pan,et al.  A miRNA-regulatory network explains how dysregulated miRNAs perturb oncogenic processes across diverse cancers , 2012, Genome research.

[61]  Pierre Hainaut,et al.  Targeting the hallmarks of cancer: towards a rational approach to next-generation cancer therapy. , 2013, Current opinion in oncology.

[62]  Alexander R. Pico,et al.  Dynamic and Coordinated Epigenetic Regulation of Developmental Transitions in the Cardiac Lineage , 2012, Cell.

[63]  Zhenggang Zhu,et al.  Overexpression of lncRNA H19 enhances carcinogenesis and metastasis of gastric cancer , 2014, Oncotarget.