The Epigenetics of Trained Immunity

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PRBB-CRG Session

by Musa Mhlanga, University of Cape Town. ZA



Coordination of pro- and anti-inflammatory processes requires tight transcriptional control. Interleukin-1 beta (IL-1ß) is a master regulator of inflammation and trained immunity. IL-1ß is encoded within the same topologically associated domain (TAD) as interleukin-37 (IL-37). IL-37 has emerged as a powerful anti-inflammatory cytokine. Within this TAD, we identified a novel long non-coding RNA, AMANZI, which negatively regulated IL-1ß expression and trained immunity by inducing IL-37 transcription through dynamic formation of long-range chromatin contacts between IL-1ß and IL-37. The formation of this dynamic contact introduces a temporal delay in IL-37 transcription, which coordinates the biphasic nature of inflammation. The common variant rs16944 augments the levels of either IL-1ß or AMANZI, predisposing individuals to enhanced pro-inflammation or immunosuppression, resulting in enhanced or diminished trained immunity. Our work illuminates a novel biphasic circuit coordinating expression of IL-1ß and IL-37, thereby regulating two functionally opposed states of inflammation from within a single TAD.


Host: Marc A. Martí-Renom


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