PU.1 Level-Directed Chromatin Structure Remodeling at the Irf8 Gene Drives Dendritic Cell Commitment
PU.1 Level-Directed Chromatin Structure Remodeling at the Irf8 Gene Drives Dendritic Cell Commitment
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DOI：
10.1016/j.celrep.2013.04.007
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发表时间：
2013-05-01
期刊：
影响因子：
8.8
通讯作者：
Rosenbauer, Frank
中科院分区：
文献类型：
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作者：
Schoenheit, Joerg;Kuhl, Christiane;Rosenbauer, Frank
树突状细胞（DC）是免疫应答的重要调节因子，然而，建立DC谱系定型的转录机制却定义不清。在这里，我们报告说，PU.1转录因子诱导干扰素调节因子8（Irf8）基因的高阶染色质结构的特异性重塑，以启动DC的命运选择。Irf8报告小鼠使我们能够精确定位初始祖细胞阶段，在该阶段DC与骨髓中的其他髓系分离。在缺乏Irf8的情况下，这种祖细胞经历DC到中性粒细胞的重编程，表明DC定型需要主动的、Irf8依赖的逃避替代性髓系潜能。从机制上讲，髓样Irf8表达依赖于高PU.1水平，导致局部染色体成环和谱系和发育阶段特异性顺式增强子的激活。这些数据将PU.1描述为通过控制调节元件之间的远距离接触来进行骨髓谱系选择的浓度依赖性变阻器，并表明Irf 8基因处特定的高级染色质重塑决定了DC分化。
Dendritic cells (DCs) are essential regulators of immune responses; however, transcriptional mechanisms that establish DC lineage commitment are poorly defined. Here, we report that the PU.1 transcription factor induces specific remodeling of the higher-order chromatin structure at the interferon regulatory factor 8 (Irf8) gene to initiate DC fate choice. An Irf8 reporter mouse enabled us to pinpoint an initial progenitor stage at which DCs separate from other myeloid lineages in the bone marrow. In the absence of Irf8, this progenitor undergoes DC-to-neutrophil reprogramming, indicating that DC commitment requires an active, Irf8-dependent escape from alternative myeloid lineage potential. Mechanistically, myeloid Irf8 expression depends on high PU.1 levels, resulting in local chromosomal looping and activation of a lineage-and developmental-stage-specific cis-enhancer. These data delineate PU.1 as a concentration-dependent rheostat of myeloid lineage selection by controlling long-distance contacts between regulatory elements and suggest that specific higher-order chromatin remodeling at the Irf8 gene determines DC differentiation.