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

Abstract

Interferon gamma (IFN-g), 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-g 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.

LncRNAs in HCV Infection and HCV-Related Liver Disease

“…The lncRNA TMEVPG1 (Theiler's murine encephalomyelitis virus persistence candidate gene 1) recently annotated as IFNG-AS1 (IFNG antisense RNA 1) was found to be downregulated in both HCV-and HDV-related HCC. This is in accordance with recent findings since IFNG-AS1 is transcribed antisense to IFNG, activating IFN-γ production, and the cellular response to viral infections by working as a chromatin structure modifier [122,139]. The three remaining lncRNAs, BC017743, BC043430, and LINC01152, are common to all viral etiologies.…”

A genome-wide association study highlights a regulatory role forIFNG-AS1contributing to cutaneous leishmaniasis in Brazil

“…and IFNG-AS1 is seen in long-lasting memory T cells, where high expression of IFNG-AS1 was associated with low IFNG suggesting that there may be feedback inhibition [30]. Here we observed that IFNG-AS1 genotype was associated with downstream effects on both the percentage of IFN--producing CD3 + T cells and the highly correlated percentage of TNF-…”

“…However, we found no evidence for expression of SERPINB10 in normal skin or in lesion biopsies, suggesting that a role in determining susceptibility to CL must be at the level of central regulation of haematopoiesis and/or immune responses. IFNG antisense RNA 1 encoded by IFNG-AS1 has been shown to finetune the magnitude of IFN- responses [30]. It is expressed in both mouse and human T helper1 cells and positively regulates Ifng expression [62,63].…”

“…Probes for IFNG-AS1 were not present on the chips used in the published microarray data [36]. Since IFNG-AS1 expression is known to influence IFN- production [30], we therefore sought functional support for this gene by examining the percent of antigen-stimulated T cells producing IFN- by IFNG-AS1 genotypes ( Figure 6 Figure 5D) with these two top hits (data not shown).…”

“…Given the important role of this long non-coding RNA (IncRNA) in determining expression of the gene IFNG encoding IFN- [30], our results provide an important novel lead to understanding pathogenesis of CL through the regulation of IFN- responses.…”