title: Transcriptome sequencing reveals thousands of novel long non-coding RNAs in B cell lymphoma.
abstract: BACKGROUND
  Gene profiling of diffuse large B cell lymphoma (DLBCL) has revealed broad gene expression deregulation compared to normal B cells. While many studies have interrogated well known and annotated genes in DLBCL, none have yet performed a systematic analysis to uncover novel unannotated long non-coding RNAs (lncRNA) in DLBCL. In this study we sought to uncover these lncRNAs by examining RNA-seq data from primary DLBCL tumors and performed supporting analysis to identify potential role of these lncRNAs in DLBCL.
  
  
  METHODS
  We performed a systematic analysis of novel lncRNAs from the poly-adenylated transcriptome of 116 primary DLBCL samples. RNA-seq data were processed using de novo transcript assembly pipeline to discover novel lncRNAs in DLBCL. Systematic functional, mutational, cross-species, and co-expression analyses using numerous bioinformatics tools and statistical analysis were performed to characterize these novel lncRNAs.
  
  
  RESULTS
  We identified 2,632 novel, multi-exonic lncRNAs expressed in more than one tumor, two-thirds of which are not expressed in normal B cells. Long read single molecule sequencing supports the splicing structure of many of these lncRNAs. More than one-third of novel lncRNAs are differentially expressed between the two major DLBCL subtypes, ABC and GCB. Novel lncRNAs are enriched at DLBCL super-enhancers, with a fraction of them conserved between human and dog lymphomas. We see transposable elements (TE) overlap in the exonic regions; particularly significant in the last exon of the novel lncRNAs suggest potential usage of cryptic TE polyadenylation signals. We identified highly co-expressed protein coding genes for at least 88 % of the novel lncRNAs. Functional enrichment analysis of co-expressed genes predicts a potential function for about half of novel lncRNAs. Finally, systematic structural analysis of candidate point mutations (SNVs) suggests that such mutations frequently stabilize lncRNA structures instead of destabilizing them.
  
  
  CONCLUSIONS
  Discovery of these 2,632 novel lncRNAs in DLBCL significantly expands the lymphoma transcriptome and our analysis identifies potential roles of these lncRNAs in lymphomagenesis and/or tumor maintenance. For further studies, these novel lncRNAs also provide an abundant source of new targets for antisense oligonucleotide pharmacology, including shared targets between human and dog lymphomas.
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, 1305 York Avenue, New York, NY, 10021, USA.|Institute for Precision Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10021, USA.|Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10021, USA.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Verma
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, 1305 York Avenue, New York, NY, 10021, USA.|Institute for Precision Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10021, USA.|Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10021, USA.|Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10021, USA.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, 1305 York Avenue, New York, NY, 10021, USA.|Institute for Precision Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10021, USA.|Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10021, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Du
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, 1305 York Avenue, New York, NY, 10021, USA.|Institute for Precision Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10021, USA.|Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10021, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Fairchild
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10021, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, 1305 York Avenue, New York, NY, 10021, USA. ole2001@med.cornell.edu.|Institute for Precision Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10021, USA. ole2001@med.cornell.edu.|Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10021, USA. ole2001@med.cornell.edu.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D004285:Dogs; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics*; D017423:Sequence Analysis, RNA; D059467:Transcriptome
chemical_list: D062085:RNA, Long Noncoding