Zhang, Q., Chao, T. C., Patil, V. S., Qin, Y., Tiwari, S. K., Chiou, J., Dobin, A., Tsai, C. M., Li, Z., Dang, J., Gupta, S., Urdahl, K., Nizet, V., Gingeras, T. R., Gaulton, K. J., Rana, T. M. (March 2019) The long noncoding RNA ROCKI regulates inflammatory gene expression. Embo j, 38 (8). Article number e100041. ISSN 0261-4189
Abstract
Long noncoding RNAs (lncRNAs) can regulate target gene expression by acting in cis (locally) or in trans (non-locally). Here, we performed genome-wide expression analysis of Toll-like receptor (TLR)-stimulated human macrophages to identify pairs of cis-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 Streptococcus We focused on elucidating the function of one lncRNA, named lnc-MARCKS or ROCKI (Regulator of Cytokines and Inflammation), which was induced by multiple TLR stimuli and acted as a master regulator of inflammatory responses. ROCKI interacted with APEX1 (apurinic/apyrimidinic endodeoxyribonuclease 1) to form a ribonucleoprotein complex at the MARCKS promoter. In turn, ROCKI-APEX1 recruited the histone deacetylase HDAC1, which removed the H3K27ac modification from the promoter, thus reducing MARCKS transcription and subsequent Ca(2+) signaling and inflammatory gene expression. Finally, genetic variants affecting ROCKI 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 cis-acting lncRNAs in TLR signaling, innate immunity, and pathophysiological inflammation.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > inflammation > cytokines bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > long non-coding RNA |
| CSHL Authors: | |
| Communities: | CSHL labs > Gingeras lab CSHL labs > Dobin Lab CSHL Cancer Center Program > Cancer Genetics and Genomics Program |
| Depositing User: | Matthew Dunn |
| Date: | 27 March 2019 |
| Date Deposited: | 09 Apr 2019 16:27 |
| Last Modified: | 05 Nov 2020 21:23 |
| PMCID: | PMC6463213 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/37766 |
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