美国加州大学圣地亚哥分校医学院Christopher K. Glass课题组的研究表明，Spalt样转录因子1（SALL1）通过增加小胶质细胞特异性DNA结合和SMAD的功能来建立小胶质细胞身份。该项研究成果发表在2023年6月15日出版的《自然—免疫学》上。

研究人员证明破坏与Sall1启动子相互作用的保守小胶质细胞特异性超级增强子，会导致小胶质细胞中Sall1表达完全缺失和细胞特异性丢失。通过确定SALL1在基因组中的结合位点并利用Sall1增强子敲除小鼠，研究人员证明小胶质细胞特异性基因表达所需的SALL1和SMAD4之间存在功能上的相互作用。SMAD4直接与Sall1超级增强子结合，并且是Sall1表达所必需的，这与果蝇翅膀中TGFβ和SMAD的同系物Dpp和Mad对Spalt细胞特异性表达调控相一致。

出乎意料的是，SALL1反过来促进SMAD4在小胶质细胞特异性增强子上的结合和功能，同时抑制SMAD4与增强子敲除小胶质细胞中不恰当激活基因增强子的结合，从而增强TGFβ-SMAD信号轴在小胶质细胞中的特异性功能。

据介绍，SALL1是器官发生和小胶质细胞身份建立的关键调节因子。

附：英文原文

Title: SALL1 enforces microglia-specific DNA binding and function of SMADs to establish microglia identity

Author: Fixsen, Bethany R., Han, Claudia Z., Zhou, Yi, Spann, Nathanael J., Saisan, Payam, Shen, Zeyang, Balak, Christopher, Sakai, Mashito, Cobo, Isidoro, Holtman, Inge R., Warden, Anna S., Ramirez, Gabriela, Collier, Jana G., Pasillas, Martina P., Yu, Miao, Hu, Rong, Li, Bin, Belhocine, Sarah, Gosselin, David, Coufal, Nicole G., Ren, Bing, Glass, Christopher K.

Issue&Volume: 2023-06-15

Abstract: Spalt-like transcription factor 1 (SALL1) is a critical regulator of organogenesis and microglia identity. Here we demonstrate that disruption of a conserved microglia-specific super-enhancer interacting with the Sall1 promoter results in complete and specific loss of Sall1 expression in microglia. By determining the genomic binding sites of SALL1 and leveraging Sall1 enhancer knockout mice, we provide evidence for functional interactions between SALL1 and SMAD4 required for microglia-specific gene expression. SMAD4 binds directly to the Sall1 super-enhancer and is required for Sall1 expression, consistent with an evolutionarily conserved requirement of the TGFβ and SMAD homologs Dpp and Mad for cell-specific expression of Spalt in the Drosophila wing. Unexpectedly, SALL1 in turn promotes binding and function of SMAD4 at microglia-specific enhancers while simultaneously suppressing binding of SMAD4 to enhancers of genes that become inappropriately activated in enhancer knockout microglia, thereby enforcing microglia-specific functions of the TGFβ–SMAD signaling axis. Glass and colleagues show that the transcription factor SALL1-associated super-enhancer is exclusively activated in microglia, in part through SMAD4-mediated signaling, and that SALL1 subsequently enforces microglia-specific functions of SMAD4.

DOI: 10.1038/s41590-023-01528-8

Source: https://www.nature.com/articles/s41590-023-01528-8