Petermann Franziska, Pękowska 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
Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA.
Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA.
Mol Cell. 2019 Sep 19;75(6):1229-1242.e5. doi: 10.1016/j.molcel.2019.06.025. Epub 2019 Jul 31.
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.
干扰素γ（IFN-γ）对宿主防御和肿瘤监测至关重要，其表达需要严格调控。Ifng周围存在多个顺式调控元件以及一个非编码转录本Ifng-as1（也称为NeST）。在此，我们描述了为剖析该基因座及其RNA产物的分子功能而构建的两种遗传模型。Ifng-as1基因座内的DNA缺失破坏了扩展的Ifng基因座的染色质组织，损害了Ifng反应，并削弱了宿主防御。聚腺苷酸信号的插入消除了Ifng-as1全长转录本并损害了宿主防御，同时允许适当的染色质结构。Ifng-as1的瞬时敲低也降低了IFN-γ的产生。在人类中，IFNG和IFNG-AS1在记忆T细胞中表达不一致，这种长链非编码RNA（lncRNA）高表达而细胞因子低表达。这些结果确立了Ifng-as1作为Ifng表达的重要调节因子，作为一种DNA元件和转录RNA，参与对感染的动态和细胞状态特异性反应。
