Abstract 364: Modulation of Novel Long Intergenic Noncoding RNAs in Human Macrophage Polarization
Macrophages respond to inflammatory stimuli by modulating gene expression. Whether long intergenic noncoding RNAs (lincRNA) play a regulatory role in human macrophage inflammatory response is unknown. Therefore, we performed RNA-Seq in human PBMC-derived macrophages (HMDM) stimulated with lipopolysaccharide (LPS) and interferon-gamma to induce M1-polarization. Of 4,662 lincRNAs (stringent set of Cabili et al, Gene & Development 2011. 25:1915-1927), expressed at 5th percentile FPKM, we identified 420 lincRNAs in HMDM or M1-HMDM, of which 58 were differentially expressed (DE) at FDR<0.01, fold change>2 (43 upregulated, 15 downregulated). Gene ontology (GO) enrichment analysis showed that M1 polarization modulated protein-coding genes involved immune response and inflammatory response. DE protein-coding genes proximal to DE lincRNAs (±100 kb) were enriched in apoptosis and cell death GO term categories. Linc-ACSL1-1 (proximal to ACSL-1), linc-MDM1-2 (proximal to IL-22), and linc-NLRP3 (proximal to NLRP3) were markedly induced, while Linc-F13A1-1 (proximal to LY86) was highly downregulated. Of SNPs from 16 GWAS of cardiometabolic diseases, 36 SNPs within the 58 DE lincRNAs reached threshold P<0.001; e.g., 16 SNPs in Linc-F13A1-1 for waist-hip ratio, with P=6.31E-09 for rs1294421. We performed complementary experiments in induced pluripotent stem cell (iPSC)-derived macrophages (IPSDM) which are functionally comparable to their isogenic primary HMDM counterparts. Analysis of DE genes in IPSDM-polarization revealed 1,527 DE genes (FDR<0.01, fold change >2) and 74% overlapped with DE genes in HMDM-polarization. Linc-ACSL1-1 and an additional 15 DE lincRNAs in IPSDM were overlapped with the DE lincRNAs in HMDM. In summary, high-resolution transcriptomics of human macrophages identified lincRNAs that form part of the cellular response during M1-polarization as well as specific lincRNAs that might modulate macrophage function in cardio-metabolic disorders.
Author Disclosures: H. Zhang: None. C. Xue: None. R.L. Ballantyne: None. R. Shah: None. K. Bermingham: None. C. Hinkle: None. W. Yang: None. S. Gosai: None. B. Gregory: None. E.E. Morrisey: None. M. Li: None. D.J. Rader: None. M.P. Reilly: None.
- © 2014 by American Heart Association, Inc.