@article{a41c89da212b4697acee1057ca7be705,
title = "The Magnitude of IFN-γ Responses Is Fine-Tuned by DNA Architecture and the Non-coding Transcript of Ifng-as1",
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",
author = "Franziska Petermann and Aleksandra P{\c e}kowska and Johnson, {Catrina A.} and Dragana Jankovic and Shih, {Han Yu} and Kan Jiang and Hudson, {William H.} and Brooks, {Stephen R.} and Sun, {Hong Wei} and Villarino, {Alejandro V.} and Chen Yao and Kentner Singleton and Akondy, {Rama S.} and Yuka Kanno and Alan Sher and Rafael Casellas and Rafi Ahmed and O'Shea, {John J.}",
note = "Funding Information: We thank members of the O{\textquoteright}Shea lab for helpful discussions, Gustavo Gutierrez-Cruz (Office of Science and Technology, NIAMS, NIH) for sequencing, and the NIAMS Flow Cytometry Group for cell sorting. We also want to thank Florian Hahne for his help with data visualization. This study utilized the high-performance computational capabilities of the Helix System at the NIH, Bethesda, MD ( https://hpc.nih.gov/ ) and was supported by NIAID and NIAMS intramural research programs and the German Research Foundation ( DFG -PE 2372/1-1 to F.P.). Funding Information: We thank members of the O'Shea lab for helpful discussions, Gustavo Gutierrez-Cruz (Office of Science and Technology, NIAMS, NIH) for sequencing, and the NIAMS Flow Cytometry Group for cell sorting. We also want to thank Florian Hahne for his help with data visualization. This study utilized the high-performance computational capabilities of the Helix System at the NIH, Bethesda, MD (https://hpc.nih.gov/) and was supported by NIAID and NIAMS intramural research programs and the German Research Foundation (DFG-PE 2372/1-1 to F.P.). F.P. designed and performed experiments, analyzed data, and wrote the manuscript. J.J.O.S. provided scientific input, supervised the project, and wrote the manuscript. All other authors performed experiments, analyzed data, and/or provided scientific input. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019",
year = "2019",
month = sep,
day = "19",
doi = "10.1016/j.molcel.2019.06.025",
language = "English (US)",
volume = "75",
pages = "1229--1242.e5",
journal = "Molecular cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}