Ou Feiya, Liu Tian-Tian, Du Siling, Chen Jing, Koch Alyssa R, Kraft Magdalena, Murphy Theresa L, Murphy Kenneth M
Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
Present address: Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
Res Sq. 2025 Sep 4:rs.3.rs-7455813. doi: 10.21203/rs.3.rs-7455813/v1.
The transcriptional regulator ID2 is required for type 1 classical dendritic cell (cDC1) specification, yet the mechanism has remained obscure. We previously identified the -165-kb enhancer as key to normal hematopoiesis, controlled by competing CEBP and NFIL3 inputs during myeloid dendritic cell divergence. Here, we uncover an unprecedented role for E proteins in myelopoiesis and demonstrate that ID2 promotes cDC1 development by antagonizing E protein activity at E-boxes within the enhancer. Deleting these E-boxes abolishes lymphoid B cell and plasmacytoid dendritic cell (pDC) development while skewing myelopoiesis toward cDC1s. Remarkably, E-box deletion rescues cDC1 development in -deficient mice. These findings support a two-step model in which NFIL3 transiently represses , followed by ID2-mediated inhibition of E proteins to stabilize cDC1 fate specification. Further, this work defines a paradigm of "site-specific pleiotropy," wherein distinct transcription factor motifs-E-boxes and CEBP sites-within a single enhancer direct diverse cell fates.
转录调节因子ID2是1型经典树突状细胞（cDC1）分化所必需的，但具体机制仍不清楚。我们之前鉴定出-165-kb增强子是正常造血的关键，在髓样树突状细胞分化过程中受竞争性的CEBP和NFIL3输入控制。在此，我们揭示了E蛋白在髓系造血中的前所未有的作用，并证明ID2通过拮抗增强子内E-boxes处的E蛋白活性促进cDC1的发育。删除这些E-boxes会消除淋巴B细胞和浆细胞样树突状细胞（pDC）的发育，同时使髓系造血偏向cDC1。值得注意的是，E-box缺失挽救了ID2缺陷小鼠中cDC1的发育。这些发现支持了一个两步模型，其中NFIL3短暂抑制增强子，随后ID2介导对E蛋白的抑制以稳定cDC1命运分化。此外，这项工作定义了一种“位点特异性多效性”模式，其中单个增强子内不同的转录因子基序——E-boxes和CEBP位点——指导不同的细胞命运。
