tRNA-like Transcripts from the NEAT1-MALAT1 Genomic Region Critically Influence Human Innate Immunity and Macrophage Functions.

The evolutionary conserved NEAT1-MALAT1 gene cluster generates large noncoding transcripts remaining nuclear, while tRNA-like transcripts (mascRNA, menRNA) enzymatically generated from these precursors translocate to the cytosol. Whereas functions have been assigned to the nuclear transcripts, data on biological functions of the small cytosolic transcripts are sparse. We previously found NEAT1-/- and MALAT1-/- mice to display massive atherosclerosis and vascular inflammation. Here, employing selective targeted disruption of menRNA or mascRNA, we investigate the tRNA-like molecules as critical components of innate immunity. CRISPR-generated human ΔmascRNA and ΔmenRNA monocytes/macrophages display defective innate immune sensing, loss of cytokine control, imbalance of growth/angiogenic factor expression impacting upon angiogenesis, and altered cell-cell interaction systems. Antiviral response, foam cell formation/oxLDL uptake, and M1/M2 polarization are defective in ΔmascRNA/ΔmenRNA macrophages, defining first biological functions of menRNA and describing new functions of mascRNA. menRNA and mascRNA represent novel components of innate immunity arising from the noncoding genome. They appear as prototypes of a new class of noncoding RNAs distinct from others (miRNAs, siRNAs) by biosynthetic pathway and intracellular kinetics. Their NEAT1-MALAT1 region of origin appears as archetype of a functionally highly integrated RNA processing system.

Genetic variants in the C-reactive protein gene are associated with microangiopathic ischemic stroke.

BACKGROUND AND PURPOSE: C-reactive protein (CRP) is an independent risk factor for cardiovascular disease and ischemic stroke. CRP serum levels are influenced by genetic variation in the CRP gene. Studies investigating the relationship between ischemic stroke and polymorphisms in the CRP gene produced equivocal results. Here we investigate single-nucleotide polymorphisms (SNPs) in the CRP gene in a large German ischemic stroke sample. METHODS: In a case-control design, 1,669 patients with ischemic stroke due to large-artery atherosclerosis, cardioembolism or cerebral microangiopathy were genotyped for 4 haplotype tagging SNPs (rs3093075, rs1205, rs1130864 and rs1800947) in the CRP gene which have been shown to influence CRP serum concentrations. Geographically matched controls were drawn from 2 prospective population-based studies, the Dortmund Health Study and the Study of Health in Pomerania. The genetic association between the SNPs and stroke was assessed using SNP and haplotype approaches. Results were adjusted for covariates by logistic regression. RESULTS: All 4 CRP SNPs reside in one linkage disequilibrium block. None of the SNPs or SNP haplotypes were associated with ischemic stroke as a whole. Three SNPs (rs3093075, rs1130864 and rs1800947) showed a significant association with microangiopathic stroke. A common 4-SNP haplotype was protective while 2 rarer haplotypes conferred susceptibility to microangiopathic stroke. All associations remained significant after adjustment for sex, age, hypertension, diabetes mellitus and hypercholesterolemia and after correction for multiple testing using the 'false discovery rate' method. CONCLUSION: Genetic variation in the CRP gene is associated with microangiopathic but not macroangiopathic or cardioembolic stroke in a large German stroke sample.