RUNX1 is required in granulocyte-monocyte progenitors to attenuate inflammatory cytokine production by neutrophils.
RUNX1 is required in granulocyte-monocyte progenitors to attenuate inflammatory cytokine production by neutrophils.
复制标题
DOI：
10.1101/gad.350418.123
复制
发表时间：
2023-07-01
影响因子：
10.5
通讯作者：
Speck, Nancy A
中科院分区：
文献类型：
--
作者：
Zezulin, Alexandra U;Yen, Daniel;Ye, Darwin;Howell, Elizabeth D;Bresciani, Erica;Diemer, Jamie;Ren, Jian-Gang;Ahmad, Mohd Hafiz;Castilla, Lucio H;Touw, Ivo P;Minn, Andy J;Tong, Wei;Liu, P Paul;Tan, Kai;Yu, Wenbao;Speck, Nancy A
在这项研究中，Zezulin等人描述了转录因子RUNX 1在粒细胞-单核细胞祖细胞和中性粒细胞中控制炎症转录程序的重要作用。RUNX 1的缺失导致TLR 4和I型IFN信号通路和逆转录因子的去抑制，导致中性粒细胞高反应性和先天性免疫疾病或恶性肿瘤。转录因子RUNX 1在家族性血小板疾病伴相关骨髓恶性肿瘤（FPDMM）和散发性骨髓增生异常综合征和白血病中突变。RUNX 1被证明可以调节多种细胞类型的炎症。在这里，我们表明，RUNX 1需要在粒细胞-单核细胞祖细胞（GMP）的表观遗传抑制两个炎症信号通路在中性粒细胞：Toll样受体4（TLR 4）和I型干扰素（IFN）信号。GMP中RUNX 1的缺失通过增加TLR 4辅助受体CD 14的表达增强了中性粒细胞对TLR 4配体脂多糖的炎症反应。RUNX 1结合Cd 14和编码TLR 4和I型IFN信号通路中的蛋白质的其他基因，当RUNX 1缺失时，这些蛋白质的染色质可及性增加。I型IFN信号传导效应子（信号转导子和转录激活子（STAT 1：：STAT 2）和干扰素调节因子（IRF））的转录因子足迹在染色质中富集，当RUNX 1丢失时，这些因子在GMP和中性粒细胞中获得了可及性。STAT 1：：STAT 2和IRF基序也在RUNX 1缺陷型GMP和中性粒细胞中去阻遏的逆转录转座子的染色质中富集。我们的结论是，一个主要的直接影响RUNX 1损失的GMP是去阻遏I型IFN和TLR 4信号，导致在一个固定的适应不良的先天免疫状态。
In this study, Zezulin et al. describe the essential role of transcription factor RUNX1 in controlling the inflammatory transcriptional program in granulocyte–monocyte progenitors and neutrophils. The loss of RUNX1 causes derepression of TLR4 and type I IFN signaling pathways and retroelements, resulting in neutrophil hyperresponsiveness and innate immunity disorders or malignancies. 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.