小柯机器人

美国圣路易斯华盛顿大学Kodi S. Ravichandran课题组通过转录暂停释放快速释放巨噬细胞的胞葬能力。2024年3月13日，《自然》杂志在线发表了这项成果。

研究人员发现巨噬细胞在遇到尸体的几分钟内就会利用转录暂停/释放来释放快速转录反应。对于人和小鼠的巨噬细胞来说，RNA聚合酶（Pol）II暂停/释放是体外和体内持续胞葬作用所必需的。有趣的是，阻断Pol II暂停/释放并不妨碍Fc受体介导的吞噬、酵母吸收或细菌吞噬。通过整合三种基因组学方法，包括精确核run-on测序、RNA测序和转座酶可进入染色质测序（ATAC-seq），在不同时间点对胞葬巨噬细胞的数据，发现Pol II暂停/释放控制着特定转录因子和下游靶基因的表达。对转录因子EGR3的机制研究发现，暂停/释放对参与细胞骨架和尸体处理的其他巨噬细胞基因的重编程与EGR3有关。

利用溶酶体探针和一种新的遗传荧光报告物，研究人员确定了暂停/释放在胞葬作用过程中吞噬体酸化的作用。此外，egr3缺陷斑马鱼胚胎的小胶质细胞对凋亡神经元的吞噬作用减弱，成熟的吞噬体减少，这支持了尸体处理缺陷。总之，这些数据表明，巨噬细胞利用Pol II暂停/释放机制迅速改变其转录程序，以有效处理摄入的凋亡尸体并进行连续的胞葬作用。

据了解，在发育、炎症或组织损伤期间，巨噬细胞可能会通过胞葬作用连续吞噬和处理多个凋亡尸体，以实现组织平衡。对于巨噬细胞如何快速调整其转录以实现连续的尸体吸收，目前尚不完全清楚。转录暂停/释放是一种演化保守的机制，其中Pol II启动20-60个核苷酸的转录，暂停数分钟至数小时，然后释放以产生全长mRNA。

附：英文原文

Title: Rapid unleashing of macrophage efferocytic capacity via transcriptional pause release

Author: Tufan, Turan, Comertpay, Gamze, Villani, Ambra, Nelson, Geoffrey M., Terekhova, Marina, Kelley, Shannon, Zakharov, Pavel, Ellison, Rochelle M., Shpynov, Oleg, Raymond, Michael, Sun, Jerry, Chen, Yitan, Bockelmann, Enno, Stremska, Marta, Peterson, Lance W., Boeckaerts, Laura, Goldman, Seth R., Etchegaray, J. Iker, Artyomov, Maxim N., Peri, Francesca, Ravichandran, Kodi S.

Issue&Volume: 2024-03-13

Abstract: During development, inflammation or tissue injury, macrophages may successively engulf and process multiple apoptotic corpses via efferocytosis to achieve tissue homeostasis1. How macrophages may rapidly adapt their transcription to achieve continuous corpse uptake is incompletely understood. Transcriptional pause/release is an evolutionarily conserved mechanism, in which RNA polymerase (Pol) II initiates transcription for 20–60 nucleotides, is paused for minutes to hours and is then released to make full-length mRNA2. Here we show that macrophages, within minutes of corpse encounter, use transcriptional pause/release to unleash a rapid transcriptional response. For human and mouse macrophages, the Pol II pause/release was required for continuous efferocytosis in vitro and in vivo. Interestingly, blocking Pol II pause/release did not impede Fc receptor-mediated phagocytosis, yeast uptake or bacterial phagocytosis. Integration of data from three genomic approaches—precision nuclear run-on sequencing, RNA sequencing, and assay for transposase-accessible chromatin using sequencing (ATAC-seq)—on efferocytic macrophages at different time points revealed that Pol II pause/release controls expression of select transcription factors and downstream target genes. Mechanistic studies on transcription factor EGR3, prominently regulated by pause/release, uncovered EGR3-related reprogramming of other macrophage genes involved in cytoskeleton and corpse processing. Using lysosomal probes and a new genetic fluorescent reporter, we identify a role for pause/release in phagosome acidification during efferocytosis. Furthermore, microglia from egr3-deficient zebrafish embryos displayed reduced phagocytosis of apoptotic neurons and fewer maturing phagosomes, supporting defective corpse processing. Collectively, these data indicate that macrophages use Pol II pause/release as a mechanism to rapidly alter their transcriptional programs for efficient processing of the ingested apoptotic corpses and for successive efferocytosis.

DOI: 10.1038/s41586-024-07172-y

Source: https://www.nature.com/articles/s41586-024-07172-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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