Trizzino Marco, Zucco Avery, Deliard Sandra, Wang Fang, Barbieri Elisa, Veglia Filippo, Gabrilovich Dmitry, Gardini Alessandro
The Wistar Institute, 3601 Spruce street, Philadelphia, PA 19104, USA.
Sci Adv. 2021 Jan 13;7(3). doi: 10.1126/sciadv.aaz8836. Print 2021 Jan.
Monocytes and monocyte-derived macrophages originate through a multistep differentiation process. First, hematopoietic stem cells generate lineage-restricted progenitors that eventually develop into peripheral, postmitotic monocytes. Second, blood-circulating monocytes undergo differentiation into macrophages, which are specialized phagocytic cells capable of tissue infiltration. While monocytes mediate some level of inflammation and cell toxicity, macrophages boast the widest set of defense mechanisms against pathogens and elicit robust inflammatory responses. Here, we analyze the molecular determinants of monocytic and macrophagic commitment by profiling the EGR1 transcription factor. EGR1 is essential for monopoiesis and binds enhancers that regulate monocytic developmental genes such as However, differentiating macrophages present a very different EGR1 binding pattern. We identify novel binding sites of EGR1 at a large set of inflammatory enhancers, even in the absence of its binding motif. We show that EGR1 repressive activity results in suppression of inflammatory genes and is mediated by the NuRD corepressor complex.
单核细胞和单核细胞衍生的巨噬细胞通过多步骤分化过程产生。首先，造血干细胞产生谱系受限的祖细胞，这些祖细胞最终发育为外周的、不再分裂的单核细胞。其次，血液循环中的单核细胞分化为巨噬细胞，巨噬细胞是能够进行组织浸润的特殊吞噬细胞。虽然单核细胞介导一定程度的炎症和细胞毒性，但巨噬细胞拥有最广泛的针对病原体的防御机制，并引发强烈的炎症反应。在这里，我们通过分析EGR1转录因子来剖析单核细胞和巨噬细胞定向分化的分子决定因素。EGR1对单核细胞生成至关重要，并结合调控单核细胞发育基因的增强子，例如……然而，正在分化的巨噬细胞呈现出非常不同的EGR1结合模式。我们在大量炎症增强子处鉴定出EGR1的新结合位点，即使在没有其结合基序的情况下也是如此。我们表明，EGR1的抑制活性导致炎症基因的抑制，并且由NuRD共抑制复合物介导。
