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bioRxiv · 10.1101/2022.03.21.485192

Chromatin-associated lncRNA Malat1 regulates Th17 effector program and promotes intestinal inflammation

Ma, S.·Zhou, B.·Chen, N.·Luo, C.·Li, Y.·Patel, P. R.·Zheng, A.·Patel, S. A.·Hao, Y.·Chang, J. T.·Fu, X.·Huang, W. J. M.
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Abstract

Interleukin IL-17 cytokines are central regulators of mucosal homeostasis and disease. In mouse models of colonic tissue injury, IL-17A promotes epithelial barrier functions and restricts local inflammation. Here, we report that IL-17A production by the diverse T lymphocyte subsets is dynamically regulated at different stages of colitis pathogenesis. During the onset and peak of the disease, T{gamma}{delta}17 cells are the major IL-17A producers, while Th17 activity is temporally restricted by long non-coding RNA (lncRNA) Malat1. In response to IL-6 and TGF{beta} signaling, Malat1 is recruited to the Th17-specific cis-regulatory elements, CNS3 and CNS4, of the Il17a locus to fine-tune bivalent super-enhancer activities and repress local transcription. During the resolution phase of inflammation, Malat1 expression is down-regulated to enhance Th17 activities, allowing Th17 cells to emerge as the main producers of IL-17A in the colonic lamina propria. Genetic ablation of Malat1 potentiates IL-17A production in Th17 cells and improves disease outcomes in mouse models of colitis. These findings uncover a surprising role of a chromatin-associated lncRNA in regulating colonic Th17-specific responses to control the timing of inflammation resolution. Significance StatementT cells are critical modulators of mucosal barrier function and inflammation. The function of long-noncoding RNAs (lncRNAs) in T cells and their role in mucosal inflammation remain elusive. Here, we identify an essential role of the lncRNA Malat1 restricting transcription of the Il17a locus in Th17 cells encoding a cytokine implicated in epithelial barrier function post-injury. By controlling the activity of the bivalent super-enhancer at the Il17a locus, Malat1 regulates the timing of inflammation resolution in the intestine. The Malat1-Il17a pathway reveals new targets for combating mucosal diseases. Graphic Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

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Ma, S., Zhou, B., Chen, N., Luo, C., Li, Y., Patel, P. R., Zheng, A., Patel, S. A., Hao, Y., Chang, J. T., Fu, X., Huang, W. J. M.. 2022-03-23. Chromatin-associated lncRNA Malat1 regulates Th17 effector program and promotes intestinal inflammation. https://doi.org/10.1101/2022.03.21.485192

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