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Mol Cell. 2019 Sep 19;75(6):1229-1242.e5. doi: 10.1016/j.molcel.2019.06.025. Epub 2019 Jul 31.

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

Author information

1
Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA.
2
Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA.
3
Immunobiology Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD 20892, USA.
4
Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
5
Biodata Mining and Discovery Section, NIAMS, NIH, Bethesda, MD 20892, USA.
6
Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA. Electronic address: kannoy@mail.nih.gov.
7
Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA. Electronic address: john.oshea@nih.gov.

Abstract

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.

KEYWORDS:

CTCF; Hi-C; IFN-γ; T helper cells; Th1; Toxoplasma gondii; cytokine; effector memory; genome architecture; lncRNA

PMID:
31377117
PMCID:
PMC6754279
[Available on 2020-09-19]
DOI:
10.1016/j.molcel.2019.06.025

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