GFI1 is a DNA-binding transcription factor that regulates hematopoiesis by repressing target genes through its association with complexes containing histone demethylases such as KDM1A (LSD1) and histone deacetylases (HDACs). To study the consequences of the disruption of the complex between GFI1 and histone-modifying enzymes, we have used knock-in mice harboring a P2A mutation in GFI1 coding region that renders it unable to bind LSD1 and associated histone-modifying enzymes such as HDACs. GFI1^P2A mice die prematurely and show increased numbers of memory effector and regulatory T cells in the spleen accompanied by a severe systemic inflammation with high serum levels of IL-6, TNF-α, and IL-1β and overexpression of the gene encoding the cytokine oncostatin M (OSM). We identified lung alveolar macrophages, CD8 T cell from the spleen and thymic eosinophils, and monocytes as the sources of these cytokines in GFI1^P2A mice. Chromatin immunoprecipitation showed that GFI1/LSD1 complexes occupy sites at the Osm promoter and an intragenic region of the Tnfα gene and that a GFI1^P2A mutant still remains bound at these sites even without LSD1. Methylation and acetylation of histone H3 at these sites were enriched in cells from GFI1^P2A mice, the H3K27 acetylation being the most significant. These data suggest that the histone modification facilitated by GFI1 is critical to control inflammatory pathways in different cell types, including monocytes and eosinophils, and that a disruption of GFI1-associated complexes can lead to systemic inflammation with fatal consequences.

GFI1 是一种 DNA 结合转录因子，它通过与含有组蛋白脱甲基酶（如 KDM1A (LSD1) 和组蛋白脱乙酰酶 (HDAC)）的复合物结合抑制靶基因来调节造血功能。为了研究 GFI1 和组蛋白修饰酶之间复合物破坏的后果，我们使用了在 GFI1 编码区携带 P2A 突变的敲入小鼠，使其无法结合 LSD1 和相关的组蛋白修饰酶，如 HDAC。GFI1 ^P2A小鼠过早死亡，脾脏中记忆效应和调节性 T 细胞数量增加，伴有严重的全身炎症，血清 IL-6、TNF-α 和 IL-1β 水平高，编码细胞因子制瘤素 M 的基因过表达(OSM)。我们在 GFI1 ^P2A小鼠中鉴定了肺泡巨噬细胞、来自脾脏和胸腺嗜酸性粒细胞的 CD8 T 细胞和单核细胞作为这些细胞因子的来源。染色质免疫沉淀表明 GFI1/LSD1 复合物占据Osm启动子和Tnf α 基因的基因内区域的位点，并且即使没有 LSD1 ，GFI1 ^P2A突变体仍保持在这些位点的结合。这些位点组蛋白 H3 的甲基化和乙酰化在来自 GFI1 的细胞中富集^P2A小鼠，H3K27 乙酰化是最重要的。这些数据表明，GFI1 促进的组蛋白修饰对于控制不同细胞类型（包括单核细胞和嗜酸性粒细胞）的炎症通路至关重要，并且 GFI1 相关复合物的破坏可导致全身性炎症，从而导致致命后果。