Expression and regulation of long noncoding RNAs in TLR4 signaling in mouse macrophages

BackgroundThough long non-coding RNAs (lncRNAs) are emerging as critical regulators of immune responses, whether they are involved in LPS-activated TLR4 signaling pathway and how is their expression regulated in mouse macrophages are still unexplored.ResultsBy repurposing expression microarray probes, we identified 994 lncRNAs in bone marrow-derived macrophages (BMDMs) and classified them to enhancer-like lncRNAs (elncRNAs) and promoter-associated lncRNAs (plncRNAs) according to chromatin signatures defined by relative levels of H3K4me1 and H3K4me3. Fifteen elncRNAs and 12 plncRNAs are differentially expressed upon LPS stimulation. The expression change of lncRNAs and their neighboring protein-coding genes are significantly correlated. Also, the regulation of both elncRNAs and plncRNAs expression is associated with H3K4me3 and H3K27Ac. Crucially, many identified LPS-regulated lncRNAs, such as lncRNA-Nfkb2 and lncRNA-Rel, locate near to immune response protein-coding genes. The majority of LPS-regulated lncRNAs had at least one binding site among the transcription factors p65, IRF3, JunB and cJun.ConclusionsWe established an integrative microarray analysis pipeline for profiling lncRNAs. Also, our results suggest that lncRNAs can be important regulators of LPS-induced innate immune response in BMDMs.

[1]  W. J. Kent,et al.  BLAT--the BLAST-like alignment tool. , 2002, Genome research.

[2]  J. Kawai,et al.  Cap analysis gene expression for high-throughput analysis of transcriptional starting point and identification of promoter usage , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Christina Gloeckner,et al.  Modern Applied Statistics With S , 2003 .

[4]  S. Salzberg,et al.  The Transcriptional Landscape of the Mammalian Genome , 2005, Science.

[5]  B. Grinde,et al.  Effect of a medicinal extract from Agaricus blazei Murill on gene expression in a human monocyte cell line as examined by microarrays and immuno assays. , 2006, International immunopharmacology.

[6]  Clifford A. Meyer,et al.  Model-based Analysis of ChIP-Seq (MACS) , 2008, Genome Biology.

[7]  S. Sunkin,et al.  Specific expression of long noncoding RNAs in the mouse brain , 2008, Proceedings of the National Academy of Sciences.

[8]  Cole Trapnell,et al.  Ultrafast and memory-efficient alignment of short DNA sequences to the human genome , 2009, Genome Biology.

[9]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[10]  Michael F. Lin,et al.  Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals , 2009, Nature.

[11]  Leonard Lipovich,et al.  Genome-wide computational identification and manual annotation of human long noncoding RNA genes. , 2010, RNA.

[12]  S. Akira,et al.  The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors , 2010, Nature Immunology.

[13]  Aaron R. Quinlan,et al.  Bioinformatics Applications Note Genome Analysis Bedtools: a Flexible Suite of Utilities for Comparing Genomic Features , 2022 .

[14]  Hideaki Sugawara,et al.  Archiving next generation sequencing data , 2009, Nucleic Acids Res..

[15]  Carsten O. Daub,et al.  Linking promoters to functional transcripts in small samples with nanoCAGE and CAGEscan , 2010, Nature Methods.

[16]  G. Kreiman,et al.  Widespread transcription at neuronal activity-regulated enhancers , 2010, Nature.

[17]  J. Ragoussis,et al.  A Large Fraction of Extragenic RNA Pol II Transcription Sites Overlap Enhancers , 2010, PLoS biology.

[18]  J. Dixon,et al.  Bcl-6 and NF-kappaB cistromes mediate opposing regulation of the innate immune response. , 2010, Genes & development.

[19]  D. Levy,et al.  A systematic comparison and evaluation of high density exon arrays and RNA-seq technology used to unravel the peripheral blood transcriptome of sickle cell disease , 2012, BMC Medical Genomics.

[20]  Howard Y. Chang,et al.  A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression , 2011, Nature.

[21]  Lana X. Garmire,et al.  A Global Clustering Algorithm to Identify Long Intergenic Non-Coding RNA - with Applications in Mouse Macrophages , 2011, PloS one.

[22]  Tao Liu,et al.  Using MACS to Identify Peaks from ChIP‐Seq Data , 2011, Current protocols in bioinformatics.

[23]  John D. Storey,et al.  Human transcriptome array for high-throughput clinical studies , 2011, Proceedings of the National Academy of Sciences.

[24]  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.

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

[26]  Changning Liu,et al.  ncFANs: a web server for functional annotation of long non-coding RNAs , 2011, Nucleic Acids Res..

[27]  R. Shiekhattar,et al.  Long non-coding RNAs and enhancers. , 2011, Current opinion in genetics & development.

[28]  Michael F. Melgar,et al.  Discovery of active enhancers through bidirectional expression of short transcripts , 2011, Genome Biology.

[29]  Tatiana A. Tatusova,et al.  NCBI Reference Sequences (RefSeq): current status, new features and genome annotation policy , 2011, Nucleic Acids Res..

[30]  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.

[31]  Kenta Nakai,et al.  DBTSS: DataBase of Transcriptional Start Sites progress report in 2012 , 2011, Nucleic Acids Res..

[32]  Michael F. Lin,et al.  Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis. , 2012, Genome research.

[33]  Anderson Chun On Tsang,et al.  Long non-coding RNA expression profiles predict clinical phenotypes in glioma , 2012, Neurobiology of Disease.

[34]  Sven Laur,et al.  Robust rank aggregation for gene list integration and meta-analysis , 2012, Bioinform..

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

[36]  G. Natoli,et al.  Noncoding transcription at enhancers: general principles and functional models. , 2012, Annual review of genetics.

[37]  Mary Goldman,et al.  The UCSC Genome Browser database: extensions and updates 2011 , 2011, Nucleic Acids Res..

[38]  D. Hume,et al.  Regulated Expression of PTPRJ/CD148 and an Antisense Long Noncoding RNA in Macrophages by Proinflammatory Stimuli , 2013, PloS one.

[39]  Sean R. Davis,et al.  NCBI GEO: archive for functional genomics data sets—update , 2012, Nucleic Acids Res..

[40]  Jeannie T. Lee,et al.  Long Noncoding RNAs: Past, Present, and Future , 2013, Genetics.

[41]  Zhonghan Li,et al.  The long noncoding RNA THRIL regulates TNFα expression through its interaction with hnRNPL , 2013, Proceedings of the National Academy of Sciences.

[42]  Zhen Su,et al.  Integrative genomic analyses reveal clinically relevant long non-coding RNA in human cancer , 2013 .

[43]  Daniel R. Caffrey,et al.  A Long Noncoding RNA Mediates Both Activation and Repression of Immune Response Genes , 2013, Science.

[44]  Shizuka Uchida,et al.  Noncoder: a web interface for exon array-based detection of long non-coding RNAs , 2012, Nucleic acids research.

[45]  Mary Goldman,et al.  The UCSC Genome Browser database: extensions and updates 2013 , 2012, Nucleic Acids Res..

[46]  Monika S. Kowalczyk,et al.  Chromatin signatures at transcriptional start sites separate two equally populated yet distinct classes of intergenic long noncoding RNAs , 2013, Genome Biology.

[47]  H. Lodish,et al.  Global discovery of erythroid long noncoding RNAs reveals novel regulators of red cell maturation. , 2014, Blood.

[48]  I. Goodhead,et al.  Long non-coding RNAs and enhancer RNAs regulate the lipopolysaccharide-induced inflammatory response in human monocytes , 2014, Nature Communications.

[49]  Daniel R. Zerbino,et al.  Ensembl 2014 , 2013, Nucleic Acids Res..

[50]  Daniel R. Caffrey,et al.  Long noncoding RNAs in innate and adaptive immunity. , 2014, Current opinion in immunology.

[51]  Stephan Mehler,et al.  Modern Applied Statistics , 2016 .