Tissue-Specific RNA-Seq in Human Evoked Inflammation Identifies Blood and Adipose LincRNA Signatures of Cardiometabolic DiseasesSignificance
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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.
- Received September 16, 2013.
- Accepted January 23, 2014.
- © 2014 American Heart Association, Inc.
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- Tissue-Specific RNA-Seq in Human Evoked Inflammation Identifies Blood and Adipose LincRNA Signatures of Cardiometabolic DiseasesSignificanceYichuan Liu, Jane F. Ferguson, Chenyi Xue, Rachel L. Ballantyne, Ian M. Silverman, Sager J. Gosai, Jacquelyn Serfecz, Michael P. Morley, Brian D. Gregory, Mingyao Li and Muredach P. ReillyArteriosclerosis, Thrombosis, and Vascular Biology. 2014;34:902-912, originally published March 19, 2014https://doi.org/10.1161/ATVBAHA.113.303123
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- Tissue-Specific RNA-Seq in Human Evoked Inflammation Identifies Blood and Adipose LincRNA Signatures of Cardiometabolic DiseasesSignificanceYichuan Liu, Jane F. Ferguson, Chenyi Xue, Rachel L. Ballantyne, Ian M. Silverman, Sager J. Gosai, Jacquelyn Serfecz, Michael P. Morley, Brian D. Gregory, Mingyao Li and Muredach P. ReillyArteriosclerosis, Thrombosis, and Vascular Biology. 2014;34:902-912, originally published March 19, 2014https://doi.org/10.1161/ATVBAHA.113.303123