期刊
MOLECULAR CELL
卷 75, 期 6, 页码 1229-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2019.06.025
关键词
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资金
- NIAID
- NIAMS
- German Research Foundation [DFG-PE 2372/1-1]
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [ZICAR041169, ZIAAR041159, ZICAR041207, ZIHAR041173] Funding Source: NIH RePORTER
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.
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