Macrophages polarize into functionally distinct subtypes while responding to microenvironmental cues. The identity of proximal transcription factors (TFs) downstream from the polarization signals are known, but their activity is typically transient, failing to explain the long-term, stable epigenomic programs developed. Here, we mapped the early and late epigenomic changes of interleukin-4 (IL-4)-induced alternative macrophage polarization. We identified the TF, early growth response 2 (EGR2), bridging the early transient and late stable gene expression program of polarization. EGR2 is a direct target of IL-4-activated STAT6, having broad action indispensable for 77% of the induced gene signature of alternative polarization, including its autoregulation and a robust, downstream TF cascade involving PPARG. Mechanistically, EGR2 binding results in chromatin opening and the recruitment of chromatin remodelers and RNA polymerase II. Egr2 induction is evolutionarily conserved during alternative polarization of mouse and human macrophages. In the context of tissue resident macrophages, Egr2 expression is most prominent in the lung of a variety of species. Thus, EGR2 is an example of an essential and evolutionarily conserved broad acting factor, linking transient polarization signals to stable epigenomic and transcriptional changes in macrophages.

中文翻译：

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转录因子EGR2是将STAT6激活与替代巨噬细胞极化的晚期稳定表观基因组程序连接的分子关键

巨噬细胞在对微环境线索作出反应的同时会极化为功能上不同的亚型。极化信号下游的近端转录因子（TFs）的身份是已知的，但它们的活性通常是瞬时的，无法解释开发的长期，稳定的表观基因组程序。在这里，我们绘制了白细胞介素4（IL-4）诱导的替代性巨噬细胞极化的早期和晚期表观基因组变化。我们确定了TF，早期生长反应2（EGR2），桥接了极化的早期瞬时和晚期稳定基因表达程序。EGR2是IL-4激活的STAT6的直接靶标，对于77％的替代极化诱导基因签名具有广泛的作用，包括其自动调节和涉及PPARG的强大的下游TF级联。机械上，在小鼠和人类巨噬细胞交替极化期间，Egr2诱导在进化上是保守的。在组织常驻巨噬细胞的背景下，Egr2表达在多种物种的肺中最为突出。因此，EGR2是必需的并且在进化上保守的广泛作用因子的一个例子，它将瞬时极化信号与巨噬细胞的稳定表观基因组和转录变化联系起来。