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

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

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1229-1242.e5
JournalMolecular cell
Volume75
Issue number6
DOIs
StatePublished - Sep 19 2019
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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