Publication Date:
2019
Description:
〈p〉Long noncoding RNAs (lncRNAs) can regulate target gene expression by acting in 〈i〉cis〈/i〉 (locally) or in 〈i〉trans〈/i〉 (non-locally). Here, we performed genome-wide expression analysis of Toll-like receptor (TLR)-stimulated human macrophages to identify pairs of 〈i〉cis〈/i〉-acting lncRNAs and protein-coding genes involved in innate immunity. A total of 229 gene pairs were identified, many of which were commonly regulated by signaling through multiple TLRs and were involved in the cytokine responses to infection by group B 〈i〉Streptococcus〈/i〉. We focused on elucidating the function of one lncRNA, named 〈i〉lnc-MARCKS〈/i〉 or 〈i〉ROCKI〈/i〉 (Regulator of Cytokines and Inflammation), which was induced by multiple TLR stimuli and acted as a master regulator of inflammatory responses. 〈i〉ROCKI〈/i〉 interacted with APEX1 (apurinic/apyrimidinic endodeoxyribonuclease 1) to form a ribonucleoprotein complex at the 〈i〉MARCKS〈/i〉 promoter. In turn, 〈i〉ROCKI〈/i〉–APEX1 recruited the histone deacetylase HDAC1, which removed the H3K27ac modification from the promoter, thus reducing 〈i〉MARCKS〈/i〉 transcription and subsequent Ca〈sup〉2+〈/sup〉 signaling and inflammatory gene expression. Finally, genetic variants affecting 〈i〉ROCKI〈/i〉 expression were linked to a reduced risk of certain inflammatory and infectious disease in humans, including inflammatory bowel disease and tuberculosis. Collectively, these data highlight the importance of 〈i〉cis〈/i〉-acting lncRNAs in TLR signaling, innate immunity, and pathophysiological inflammation.〈/p〉
Print ISSN:
0261-4189
Electronic ISSN:
1460-2075
Topics:
Biology
,
Medicine
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