The Magnitude of IFN-γ Responses Is Fine-Tuned by DNA Architecture and the Non-coding Transcript of Ifng-as1.

Autor:	Petermann F; Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA., Pękowska A; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Johnson CA; Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA., Jankovic D; Immunobiology Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD 20892, USA., Shih HY; Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA., Jiang K; Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA., Hudson WH; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA., Brooks SR; Biodata Mining and Discovery Section, NIAMS, NIH, Bethesda, MD 20892, USA., Sun HW; Biodata Mining and Discovery Section, NIAMS, NIH, Bethesda, MD 20892, USA., Villarino AV; Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA., Yao C; Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA., Singleton K; Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA., Akondy RS; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA., Kanno Y; Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA. Electronic address: kannoy@mail.nih.gov., Sher A; Immunobiology Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD 20892, USA., Casellas R; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Ahmed R; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA., O'Shea JJ; Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA. Electronic address: john.oshea@nih.gov.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2019 Sep 19; Vol. 75 (6), pp. 1229-1242.e5. Date of Electronic Publication: 2019 Jul 31.
DOI:	10.1016/j.molcel.2019.06.025
Abstrakt:	Interferon gamma (IFN-γ), critical for host defense and tumor surveillance, requires tight control of its expression. Multiple cis-regulatory elements exist around Ifng along with a non-coding transcript, Ifng-as1 (also termed NeST). Here, we describe two genetic models generated to dissect the molecular functions of this locus and its RNA product. DNA deletion within the Ifng-as1 locus disrupted chromatin organization of the extended Ifng locus, impaired Ifng response, and compromised host defense. Insertion of a polyA signal ablated the Ifng-as1 full-length transcript and impaired host defense, while allowing proper chromatin structure. Transient knockdown of Ifng-as1 also reduced IFN-γ production. In humans, discordant expression of IFNG and IFNG-AS1 was evident in memory T cells, with high expression of this long non-coding RNA (lncRNA) and low expression of the cytokine. These results establish Ifng-as1 as an important regulator of Ifng expression, as a DNA element and transcribed RNA, involved in dynamic and cell state-specific responses to infection. (Published by Elsevier Inc.)
Databáze:	MEDLINE
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