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

Interleukin IL-17 cytokines are central regulators of mucosal homeostasis and disease. In response to tissue injury, IL-17A promotes epithelial barrier functions and restricts local inflammation. In the resolution phase of colonic inflammation, adaptive Th17 cells are the major source of IL-17A, however, the cell-specific temporal control mechanism(s) underlying the delayed Th17 response remain elusive. Here, we discover a surprising role of the lncRNA Malat1 as a key barrier to achieving a robust and protective Th17 response. Genetic ablation of Malat1 potentiates IL-17A production in Th17 cells and improves disease outcomes in mouse models of colitis. Mechanistically, Malat1 represses Il17a transcription by restricting its bivalent super-enhancer activities. Thus, Malat1 is down-regulated during the resolution phase of inflammation, allowing Th17 to overtake early Tγδ17 as the major source of colonic IL-17A. Targeted depletion of Malat1 in T helper cell using anti-sense nucleotides show therapeutic potential in colitis model. ### Competing Interest Statement The authors have declared no competing interest.