Identifying a locus in super-enhancer and its resident NFE2L1/MAFG as transcriptional factors that drive PD-L1 expression and immune evasion.
Identifying a locus in super-enhancer and its resident NFE2L1/MAFG as transcriptional factors that drive PD-L1 expression and immune evasion.
复制标题
确定超级增强子中的一个基因座及其所含的转录因子NFE2L1/MAFG，它们可驱动程序性死亡配体1（PD-L1）的表达并促使肿瘤发生免疫逃逸。
DOI：
10.1038/s41389-023-00500-3
复制
发表时间：
2023-11-20
期刊：
影响因子：
6.2
通讯作者：
Fan, Yihui
中科院分区：
文献类型：
--
作者：
Shi, Conglin;Chen, Liuting;Pi, Hui;Cui, Henglu;Fan, Chenyang;Tan, Fangzheng;Qu, Xuanhao;Sun, Rong;Zhao, Fengbo;Song, Yihua;Wu, Yuanyuan;Chen, Miaomiao;Ni, Wenkai;Qu, Lishuai;Mao, Renfang;Fan, Yihui
尽管程序性死亡配体1（PD-L1）启动子的转录调控已被广泛研究，但存在于PD-L1超级增强子中的转录因子尚未被全面探索。通过对PD-L1超级增强子核心区域的饱和CRISPR-Cas9筛选，我们已经确定了一个关键的遗传基因座，称为基因座22，它对PD-L1表达至关重要。位点22是NFE 2：MAF转录因子的潜在结合位点。虽然NRF 2（NFE 2L 2）的遗传沉默不会导致PD-L1表达的降低，但进一步的分析表明，MAFG和NFE 2L 1（NRF 1）在PD-L1的表达中起着关键作用。重要的是，脂多糖（LPS）作为肿瘤内细菌的主要成分可以极大地诱导PD-L1表达，这依赖于PD-L1超级增强子，位点22和NFE 2L 1/MAFG。从机制上讲，基因座22的遗传修饰和MAFG的沉默大大降低了BRD 4结合和环形成，但对H3 K27 Ac修饰的影响最小。与对照细胞不同，具有基因座22的遗传修饰和NFE 2L 1/MAFG沉默的细胞未能逃脱T细胞介导的杀伤。在乳腺癌中，MAFG的表达与PD-L1的表达呈正相关。综上所述，我们的研究结果证明了位点22及其相关转录因子NFE 2L 1/MAFG在超级增强子和LPS诱导的PD-L1表达中的关键作用。我们的研究结果为理解PD-L1转录的调控和肿瘤内细菌介导的免疫逃避提供了新的见解。
Although the transcriptional regulation of the programmed death ligand 1 (PD-L1) promoter has been extensively studied, the transcription factor residing in the PD-L1 super-enhancer has not been comprehensively explored. Through saturated CRISPR-Cas9 screening of the core region of the PD-L1 super-enhancer, we have identified a crucial genetic locus, referred to as locus 22, which is essential for PD-L1 expression. Locus 22 is a potential binding site for NFE2:MAF transcription factors. Although genetic silencing of NRF2 (NFE2L2) did not result in a reduction of PD-L1 expression, further analysis reveals that MAFG and NFE2L1 (NRF1) play a critical role in the expression of PD-L1. Importantly, lipopolysaccharides (LPS) as the major component of intratumoral bacteria could greatly induce PD-L1 expression, which is dependent on the PD-L1 super-enhancer, locus 22, and NFE2L1/MAFG. Mechanistically, genetic modification of locus 22 and silencing of MAFG greatly reduce BRD4 binding and loop formation but have minimal effects on H3K27Ac modification. Unlike control cells, cells with genetic modification of locus 22 and silencing of NFE2L1/MAFG failed to escape T cell-mediated killing. In breast cancer, the expression of MAFG is positively correlated with the expression of PD-L1. Taken together, our findings demonstrate the critical role of locus 22 and its associated transcription factor NFE2L1/MAFG in super-enhancer– and LPS-induced PD-L1 expression. Our findings provide new insight into understanding the regulation of PD-L1 transcription and intratumoral bacteria-mediated immune evasion.
登录
查看更多内容
DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
影响因子：
30.8
作者：
Papalexi E;Mimitou EP;Butler AW;Foster S;Bracken B;Mauck WM 3rd;Wessels HH;Hao Y;Yeung BZ;Smibert P;Satija R
通讯作者：
Satija R
影响因子：
5.3
作者：
Motohashi, Hozumi;Fujita, Rie;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki
影响因子：
24.8
作者：
Mirji, Gauri;Worth, Alison;Bhat, Sajad Ahmad;El Sayed, Mohamed;Kannan, Toshitha;Goldman, Aaron R.;Tang, Hsin-Yao;Liu, Qin;Auslander, Noam;Dang, Chi, V;Abdel-Mohsen, Mohamed;Kossenkov, Andrew;Stanger, Ben Z.;Shinde, Rahul S.
通讯作者：
Shinde, Rahul S.
DOI：
10.1006/bbrc.1997.6943
发表时间：
1997-07-18
影响因子：
3.1
作者：
Itoh, K;Chiba, T;Nabeshima, Y
通讯作者：
Nabeshima, Y