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Restraint of IFN-γ expression through a distal silencer CNS–28 for tissue homeostasis

ABSTRACT: Interferon-gamma (IFN-gamma) is a key cytokine in response to viral or intracellular bacterial infection in mammals. While a number of enhancers are described to promote IFN-gamma responses, no silencers for the Ifng gene have been identified. By examining H3K4me1 histone modification in naïve CD4+ T cells within Ifng locus, we identified an unrecognized silencer (CNS–28) that is responsible for restraining Ifng expression. Mechanistic study further demonstrates that CNS–28 maintains Ifng silence by diminishing enhancer-promoter interactions within Ifng locus in a T-bet independent manner. Functionally, CNS–28 restrains Ifng transcription in Th1, Tc1, and NK cells during both innate and adaptive immune responses. Moreover, CNS–28 deficiency resulted in repressed type 2 responses due to elevated IFN-gamma 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE204946 | GEO | 2023/03/01

REPOSITORIES: GEO

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The magnitude of IFN-g responses is fine-tuned by DNA architecture and the non-coding transcript of Ifng-as1

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2019-07-19 | GSE132531 | GEO

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2022-12-10 | GSE218132 | GEO

Distinct roles for IL-27 and IFN-g in the development of T-bet+ Treg required to limit infection-induced pathology

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