RUNX1转录因子在与骨髓增生异常综合征和白血病相关的家族性血小板紊乱症 (Familial platelet disorder with associated myeloid malignancy，FPDMM)以及散发性骨髓增殖异常综合征和白血病中发生突变。已证明RUNX1能够调节多种细胞类型中的炎症反应。在这里，我们展示了RUNX1在粒细胞-单核细胞前体 (Granulocyte-Monocyte Progenitors, GMPs) 中的必要性，以在中性粒细胞中表观遗传抑制两个炎症信号通路：Toll样受体4 (Toll-like Receptor 4, TLR4) 和类型I干扰素 (Type I Interferon, IFN) 信号通路。GMPs中的RUNX1缺失通过增加TLR4共受体CD14的表达，增强了中性粒细胞对TLR4配体脂多糖 (Lipopolysaccharide, LPS) 的炎症反应。当RUNX1删除后，与TLR4和类型I干扰素信号通路中的编码蛋白的基因结合的Cd14和其他基因的染色质可及性增加。当RUNX1丧失时，粒细胞-单核细胞前体和中性粒细胞中获得可及性的染色质富集了类型I干扰素信号转导蛋白（Signal Transducer and Activator of Transcription, STAT1::STAT2）和干扰素调节因子 (Interferon Regulatory Factors, IRFs) 的转录因子足迹。STAT1::STAT2和IRF位点也富集在RUNX1缺失的GMPs和中性粒细胞的转座子染色质中。我们得出结论，RUNX1在GMPs中的缺失的一个重要直接效应是类型I干扰素和TLR4信号通路的解抑制，导致固定的失调先天免疫状态。© 2023 Zezulin et al.; 由Cold Spring Harbor Laboratory Press出版。

The transcription factor RUNX1 is mutated in familial platelet disorder with associated myeloid malignancy (FPDMM) and in sporadic myelodysplastic syndrome and leukemia. RUNX1 was shown to regulate inflammation in multiple cell types. Here we show that RUNX1 is required in granulocyte-monocyte progenitors (GMPs) to epigenetically repress two inflammatory signaling pathways in neutrophils: Toll-like receptor 4 (TLR4) and type I interferon (IFN) signaling. RUNX1 loss in GMPs augments neutrophils' inflammatory response to the TLR4 ligand lipopolysaccharide through increased expression of the TLR4 coreceptor CD14. RUNX1 binds Cd14 and other genes encoding proteins in the TLR4 and type I IFN signaling pathways whose chromatin accessibility increases when RUNX1 is deleted. Transcription factor footprints for the effectors of type I IFN signaling-the signal transducer and activator of transcription (STAT1::STAT2) and interferon regulatory factors (IRFs)-were enriched in chromatin that gained accessibility in both GMPs and neutrophils when RUNX1 was lost. STAT1::STAT2 and IRF motifs were also enriched in the chromatin of retrotransposons that were derepressed in RUNX1-deficient GMPs and neutrophils. We conclude that a major direct effect of RUNX1 loss in GMPs is the derepression of type I IFN and TLR4 signaling, resulting in a state of fixed maladaptive innate immunity.© 2023 Zezulin et al.; Published by Cold Spring Harbor Laboratory Press.