Dissecting the Role of a lncRNA and Involvement of Plasmodium Infections in the Innate Immune Response: A Dissertation

Natural antisense transcripts (NATs) are a class of long noncoding RNAs (lncRNAs) that are complementary to other protein-coding genes. Although thousands of NATs are encoded by mammalian genomes, their functions in innate immunity are unknown. Here, we identify and characterize a novel NAT, AS-IL1α that is partially complementary to IL-1α. Similar to IL-1α, AS-IL1α is expressed at low levels in resting macrophages and is induced following infection with Listeria monocytogenes or stimulation with TLR ligands (Pam3CSK4, LPS, PolyI:C). Inducible expression of IL-1α mRNA and protein were significantly reduced in macrophages expressing shRNA that target AS-IL1α. AS-IL1α does not alter the stability of IL-1α mRNA, as expected of many natural antisense transcripts. Instead, AS-IL1α was required for the recruitment of RNA Polymerase II (RNAPII) to the IL-1α promoter to initiate transcription in the nucleus. In summary, our studies identify AS-IL1α as important regulator of IL1α transcription during the inflammatory response.