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

• Type of Material: Article
• Authors: Franziska Petermann, National Institute of Arthritis and Musculoskeletal and Skin Disease; Aleksandra Pekowska, National Institute of Arthritis and Musculoskeletal and Skin Disease; Catrina A. Johnson, National Institute of Arthritis and Musculoskeletal and Skin Disease; Dragana Jankovic, National Institute of Allergy and Infectious Diseases; Han-Yu Shih, National Institute of Arthritis and Musculoskeletal and Skin Disease; Kan Jiang, National Institute of Arthritis and Musculoskeletal and Skin Disease; William Hudson, Emory University; Stephen R. Brooks, National Institute of Arthritis and Musculoskeletal and Skin Disease; Hong-Wei Sun, National Institute of Arthritis and Musculoskeletal and Skin Disease; Alejandro V. Villarino, National Institute of Arthritis and Musculoskeletal and Skin Disease; Chen Yao, National Institute of Arthritis and Musculoskeletal and Skin Disease; Kentner Singleton, National Institute of Arthritis and Musculoskeletal and Skin Disease; Rama Akondy, Emory University; Yuka Kanno, National Institute of Arthritis and Musculoskeletal and Skin Disease; Alan Sher, National Institute of Allergy and Infectious Diseases; Rafael Casellas, National Institute of Arthritis and Musculoskeletal and Skin Disease; Rafi Ahmed, Emory University; John J. O'Shea, National Institute of Arthritis and Musculoskeletal and Skin Disease
• Language: English
• Date: 2019-09-19
• Publisher: CELL PRESS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.molcel.2019.06.025
• Title of Journal or Parent Work: MOLECULAR CELL
• Volume: 75
• Issue: 6
• Start Page: 1229
• End Page: +
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cell Biology; Biochemistry & Molecular Biology; CHROMATIN DOMAINS; SUSCEPTIBILITY; THEILERS-VIRUS; GENE; MEMORY; PERSISTENCE; EXPRESSION; INTERFERON-GAMMA; RNAS; EVOLUTION

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.