The synergistic activation mediator (SAM) system can robustly activate endogenous gene expression by a single-guide RNA. This transcriptional modulation has been shown to enhance gene promoter activity and leads to epigenetic changes. Human interferon-γ is a common natural glycoprotein involved in antiviral effects and inhibition of cancer cell growth. Large quantities of high-purity interferon-γ are important for medical research and clinical therapy. To investigate the possibility of employing the SAM system to enhance endogenous human interferon-γ with normal function in innate immunity, we designed 10 single-guide RNAs that target 200 bp upstream of the transcription start sites of the interferon-γ genome, which could significantly activate the interferon-γ promoter reporter. We confirmed that the system can effectively and highly activate interferon-γ expression in several humanized cell lines. Moreover, we found that the interferon-γ induced by the SAM system could inhibit tumorigenesis. Taken together, our results reveal that the SAM system can modulate epigenetic traits of non-immune cells through activating interferon-γ expression and triggering JAK-STAT signaling pathways. Thus, this strategy could offer a novel approach to inhibit tumorigenesis without using exogenous interferon-γ.

中文翻译：

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协同激活介体衍生系统诱导的干扰素-γ的特定表达激活先天免疫力并抑制肿瘤发生。

协同激活介体（SAM）系统可以通过单向导RNA牢固地激活内源基因表达。已经表明这种转录调节增强基因启动子活性并导致表观遗传学变化。人干扰素-γ是一种常见的天然糖蛋白，参与抗病毒作用和抑制癌细胞生长。大量高纯度干扰素-γ对医学研究和临床治疗很重要。为了研究使用SAM系统增强先天免疫中具有正常功能的内源性人干扰素-γ的可能性，我们设计了10个单向导RNA，其靶向干扰素-γ基因组转录起始位点上游200 bp。激活γ-干扰素启动子。我们证实该系统可以有效和高度激活几种人源化细胞系中的γ-干扰素表达。此外，我们发现SAM系统诱导的干扰素-γ可以抑制肿瘤发生。两者合计，我们的结果表明，SAM系统可以通过激活干扰素γ的表达和触发JAK-STAT信号通路来调节非免疫细胞的表观遗传特性。因此，该策略可以提供一种无需使用外源性干扰素-γ即可抑制肿瘤发生的新方法。我们的结果表明，SAM系统可以通过激活干扰素γ的表达和触发JAK-STAT信号通路来调节非免疫细胞的表观遗传特性。因此，该策略可以提供一种无需使用外源性干扰素-γ即可抑制肿瘤发生的新方法。我们的结果表明，SAM系统可以通过激活干扰素-γ的表达和触发JAK-STAT信号通路来调节非免疫细胞的表观遗传特性。因此，该策略可以提供一种无需使用外源性干扰素-γ即可抑制肿瘤发生的新方法。