biostudies-literatureCui KIntramural NIH HHSNIGMS NIH HHS944-958.e6https://www.ebi.ac.uk/biostudies/studies/S-EPMC10175192biostudies-literatureUnknown56(5)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 tyImmunityRestraint of IFN-γ expression through a distal silencer CNS-28 for tissue homeostasis.PMC10175192P20 GM121322ZIA BC011801Ren GCui KZhu JChen ZFang DHu GWei DCao YWu CLiu SLiu CZhao KfalseRestraint of IFN-γ expression through a distal silencer CNS-28 for tissue homeostasis.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 ty2023-01-01T00:00:00Z2023 May2026-06-01T20:23:35.567Z2026-05-20T03:07:48.901ZS-EPMC101751923704076110.1016/j.immuni.2023.03.006