Transcription Factor IRF8 Governs Enhancer Landscape Dynamics in Mononuclear Phagocyte Progenitors
Transcription Factor IRF8 Governs Enhancer Landscape Dynamics in Mononuclear Phagocyte Progenitors
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转录因子IRF8调控单核吞噬细胞祖细胞中增强子景观动态
DOI：
10.1016/j.celrep.2018.02.048
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发表时间：
2018-03-06
期刊：
影响因子：
8.8
通讯作者：
Tamura, Tomohiko
中科院分区：
文献类型：
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作者：
Kurotaki, Daisuke;Nakabayashi, Jun;Tamura, Tomohiko
单核细胞和树突状细胞（DC）是免疫应答所必需的单核吞噬细胞，其通过单核细胞- DC祖细胞（MDP）从造血干细胞发育而来。其发展的分子基础仍不清楚。由于启动子远端增强子是决定细胞命运的关键，我们分析了体内单核吞噬细胞发育过程中的增强子景观。单核细胞和DC特异性增强子在相关基因表达之前的祖细胞阶段逐渐建立。在预测与这些增强子结合的转录因子中，发现单核细胞和DC发育所必需的IRF 8是建立这些增强子所必需的，特别是单核细胞和DC谱系共同的那些。虽然Irf 8（-/-）单核吞噬细胞祖细胞，包括MDP，显示非常正常的基因表达模式，其增强子景观类似于上游祖细胞群体。我们的研究结果说明了关键转录因子调节增强子形成的动态过程，因此，指导未来的基因表达，以实现单核吞噬细胞的发展。
Monocytes and dendritic cells (DCs), mononuclear phagocytes essential for immune responses, develop from hematopoietic stem cells via monocyte- DC progenitors (MDPs). The molecular basis of their development remains unclear. Because promoter-distal enhancers are key to cell fate decisions, we analyzed enhancer landscapes during mononuclear phagocyte development in vivo. Monocyteand DC-specific enhancers were gradually established at progenitor stages before the expression of associated genes. Of the transcription factors predicted to bind to these enhancers, IRF8, essential for monocyte and DC development, was found to be required for the establishment of these enhancers, particularly those common to both monocyte and DC lineages. Although Irf8(-/-) mononuclear phagocyte progenitors, including MDPs, displayed grossly normal gene expression patterns, their enhancer landscapes resembled that of an upstream progenitor population. Our results illustrate the dynamic process by which key transcription factors regulate enhancer formation and, therefore, direct future gene expression to achieve mononuclear phagocyte development.