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

Authors：Petermann, Franziska; Pekowska, Aleksandra; Johnson, Catrina A; Jankovic, Dragana; Shih, Han Yu; Jiang, Kan; Hudson, William H; Brooks, Stephen R; Sun, Hong Wei; Villarino, Alejandro V; Yao, Chen; Singleton, Kentner; Akondy, Rama S; Kanno, Yuka^*; Sher, Alan; Casellas, Rafael; Ahmed, Rafi; O'Shea, John J^*

Source：Molecular Cell, 2019.

DOI：10.1016/j.molcel.2019.06.025

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

Interferon gamma (IFN-gamma), 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-gamma 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.