title: Tissue-specific RNA-Seq in human evoked inflammation identifies blood and adipose LincRNA signatures of cardiometabolic diseases.
abstract: OBJECTIVE
  Inappropriate transcriptional activation of innate immunity is a pathological feature of several cardiometabolic disorders, but little is known about inflammatory modulation of long intergenic noncoding RNAs (lincRNAs) in disease-relevant human tissues.
  
  
  RESULTS
  We applied deep RNA sequencing (>500 million filtered reads per sample) to blood and adipose during low-dose experimental endotoxemia (lipopolysaccharide) in a healthy human, with targeted replication in separate individuals undergoing endotoxemia (n=6), to identify inflammatory lincRNAs. A subset of these lincRNAs was examined for expression in adipocytes and monocytes, modulation in adipose of obese humans, and overlap with genome-wide association study signals for inflammatory and cardiometabolic traits. Of a stringent set of 4284 lincRNAs, ≈11% to 22% were expressed with 201 and 56 lincRNAs modulated by lipopolysaccharide in blood or adipose, respectively. Tissue-specific expression of a subset of 6 lipopolysaccharide-lincRNAs was replicated with lipopolysaccharide modulation confirmed for all 3 expressed in blood and 2 of 4 expressed in adipose. The broader generalizability of findings in blood of subject A was confirmed by RNA sequencing in 7 additional subjects. We confirmed adipocytes and monocytes as potential cell-sources of selective lipopolysaccharide-regulated lincRNAs, and 2 of these, linc-DMRT2 (P=0.002) and linc-TP53I13 (P=0.01), were suppressed in adipose of obese humans. Finally, we provide examples of lipopolysaccharide-modulated lincRNAs that overlap single nucleotide polymorphisms that are associated with cardiometabolic traits.
  
  
  CONCLUSIONS
  Our findings provide novel insights into tissue-level, inflammatory transcriptome regulation in cardiometabolic diseases. These are complementary to more usual approaches limited to interrogation of DNA variations.
authors: From the Departments of Biostatistics and Epidemiology and Biology, Cardiovascular Institute, Perelman School of Medicine and School of Arts and Science at the University of Pennsylvania, Philadelphia.
authors: Yichuan
authors: Y
authors: Liu
authors: Jane F
authors: JF
authors: Ferguson
authors: Chenyi
authors: C
authors: Xue
authors: Rachel L
authors: RL
authors: Ballantyne
authors: Ian M
authors: IM
authors: Silverman
authors: Sager J
authors: SJ
authors: Gosai
authors: Jacquelyn
authors: J
authors: Serfecz
authors: Michael P
authors: MP
authors: Morley
authors: Brian D
authors: BD
authors: Gregory
authors: Mingyao
authors: M
authors: Li
authors: Muredach P
authors: MP
authors: Reilly
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000328:Adult; D001665:Binding Sites; D016022:Case-Control Studies; D002478:Cells, Cultured; D019446:Endotoxemia / Q000097:blood / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000235:genetics*; D018836:Inflammation Mediators / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000235:genetics*; D009000:Monocytes / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000235:genetics; D062085:RNA, Long Noncoding / Q000097:blood*; D015203:Reproducibility of Results; D017423:Sequence Analysis, RNA / Q000379:methods*; D050151:Subcutaneous Fat / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D055815:Young Adult
chemical_list: D005819:Genetic Markers; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D062085:RNA, Long Noncoding; D014157:Transcription Factors
keywords: RNA sequence; genomics; lincRNA