美国圣路易斯华盛顿大学Kenneth M. Murphy研究团队鉴定到Nfil3–Zeb2–Id2通路在cDC1细胞发育期间参与调控Irf8增强子的转换。该研究于2019年9月发表于国际一流学术期刊《自然—免疫学》杂志上。

经典的1型树突细胞（cDC1）是抗病毒和抗肿瘤免疫所必需的，因此需要去了解它们的发育过程。cDC1祖细胞的发育需要一个E-蛋白依赖的增强子，其位于转录因子Irf8转录起始位点下游41千碱基（kb）处，但其成熟反而需要Batf3依赖的Irf8下游32kb处的增强子。

为了理解这种转换，研究人员对共同的树突细胞祖细胞（CDP）进行了单细胞RNA测序，并鉴定了一群细胞，其表达影响cDC1发育的转录因子，如Nfil3、Id2和Zeb2。这些因子中的遗传上位性揭示Nfil3表达是从Zeb2hi和Id2lo CDP向Zeb2lo和Id2hi CDP转变所必需的，其代表最早定型的cDC1祖细胞。该遗传回路通过阻断E-蛋白活性来遏制浆细胞样树突状细胞分化潜力，并解释了cDC1发育过程中Irf8增强子使用的转换。

附：英文原文

Title: An Nfil3 – Zeb2 – Id2 pathway imposes Irf8 enhancer switching during cDC1 development

Author: Prachi Bagadia, Xiao Huang, Tian-Tian Liu, Vivek Durai, Gary E. Grajales-Reyes, Maximilian Nitschk, Zora Modrusan, Jeffrey M. Granja, Ansuman T. Satpathy, Carlos G. Briseo, Marco Gargaro, Arifumi Iwata, Sunkyung Kim, Howard Y. Chang, Andrey S. Shaw, Theresa L. Murphy, Kenneth M. Murphy

Issue&Volume: Volume 20 Issue 9

Abstract: Classical type 1 dendritic cells (cDC1s) are required for antiviral and antitumor immunity, which necessitates an understanding of their development. Development of the cDC1 progenitor requires an E-protein-dependent enhancer located 41 kilobases downstream of the transcription start site of the transcription factor Irf8 (+41-kb Irf8 enhancer), but its maturation instead requires the Batf3-dependent +32-kb Irf8 enhancer. To understand this switch, we performed single-cell RNA sequencing of the common dendritic cell progenitor (CDP) and identified a cluster of cells that expressed transcription factors that influence cDC1 development, such as Nfil3, Id2 and Zeb2. Genetic epistasis among these factors revealed that Nfil3 expression is required for the transition from Zeb2hi and Id2lo CDPs to Zeb2lo and Id2hi CDPs, which represent the earliest committed cDC1 progenitors. This genetic circuit blocks E-protein activity to exclude plasmacytoid dendritic cell potential and explains the switch in Irf8 enhancer usage during cDC1 development.

DOI: 10.1038/s41590-019-0449-3

Source:https://www.nature.com/articles/s41590-019-0449-3