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24504737
Tissue-specific RNA-Seq in human evoked inflammation identifies blood and adipose LincRNA signatures of cardiometabolic diseases.

Arterioscler Thromb Vasc Biol, 2014/4;34(4):902-12.

Liu Y[1], Ferguson JF, Xue C, Ballantyne RL, Silverman IM, Gosai SJ, Serfecz J, Morley MP, Gregory BD, Li M, Reilly MP

Affiliations

PMID: 24504737DOI: 10.1161/ATVBAHA.113.303123

Impact factor: 10.514

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.
approach and 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.

Keywords: RNA sequence; genomics; lincRNA

MeSH terms
Adipocytes; Adult; Binding Sites; Case-Control Studies; Cells, Cultured; Endotoxemia; Female; Gene Expression Profiling; Gene Expression Regulation; Genetic Markers; Genome-Wide Association Study; High-Throughput Nucleotide Sequencing; Humans; Inflammation; Inflammation Mediators; Lipopolysaccharides; Male; Metabolic Syndrome; Monocytes; Obesity; RNA, Long Noncoding; Reproducibility of Results; Sequence Analysis, RNA; Subcutaneous Fat; Transcription Factors; Young Adult
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