Restraint of IFN-γ expression through a distal silencer CNS-28 for tissue homeostasis
- PMID: 37040761
- PMCID: PMC10175192
- DOI: 10.1016/j.immuni.2023.03.006
Restraint of IFN-γ expression through a distal silencer CNS-28 for tissue homeostasis
Abstract
Interferon-γ (IFN-γ) is a key cytokine in response to viral or intracellular bacterial infection in mammals. While a number of enhancers are described to promote IFN-γ responses, to the best of our knowledge, no silencers for the Ifng gene have been identified. By examining H3K4me1 histone modification in naive CD4+ T cells within Ifng locus, we identified a silencer (CNS-28) that restrains Ifng expression. Mechanistically, CNS-28 maintains Ifng silence by diminishing enhancer-promoter interactions within Ifng locus in a GATA3-dependent but T-bet-independent manner. Functionally, CNS-28 restrains Ifng transcription in NK cells, CD4+ cells, and CD8+ T cells during both innate and adaptive immune responses. Moreover, CNS-28 deficiency resulted in repressed type 2 responses due to elevated IFN-γ expression, shifting Th1 and Th2 paradigm. Thus, CNS-28 activity ensures immune cell quiescence by cooperating with other regulatory cis elements within the Ifng gene locus to minimize autoimmunity.
Keywords: IFN-gamma expression; chromatin interaction; distal enhancer; distal repressor of transcription; tissue homeostasis.
Published by Elsevier Inc.
Conflict of interest statement
Declaration of interests The authors declare no competing interests.
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Comment in
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To loop or not to loop? CNS-28 is the answer.Immunity. 2023 May 9;56(5):895-897. doi: 10.1016/j.immuni.2023.04.009. Immunity. 2023. PMID: 37163987
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