INSERM U1170, Gustave Roussy Cancer Center, 94805, Villejuif, France.
Faculté de Médecine, Université Paris-Sud, 94270, Le Kremlin-Bicêtre, France.
Nat Commun. 2019 Apr 26;10(1):1935. doi: 10.1038/s41467-019-09970-9.
Despite their location at the cell surface, several receptor tyrosine kinases (RTK) are also found in the nucleus, as either intracellular domains or full length proteins. However, their potential nuclear functions remain poorly understood. Here we find that a fraction of full length Colony Stimulating Factor-1 Receptor (CSF-1R), an RTK involved in monocyte/macrophage generation, migrates to the nucleus upon CSF-1 stimulation in human primary monocytes. Chromatin-immunoprecipitation identifies the preferential recruitment of CSF-1R to intergenic regions, where it co-localizes with H3K4me1 and interacts with the transcription factor EGR1. When monocytes are differentiated into macrophages with CSF-1, CSF-1R is redirected to transcription starting sites, colocalizes with H3K4me3, and interacts with ELK and YY1 transcription factors. CSF-1R expression and chromatin recruitment is modulated by small molecule CSF-1R inhibitors and altered in monocytes from chronic myelomonocytic leukemia patients. Unraveling this dynamic non-canonical CSF-1R function suggests new avenues to explore the poorly understood functions of this receptor and its ligands.
尽管几种受体酪氨酸激酶 (RTK) 位于细胞表面，但也有一些作为细胞内结构域或全长蛋白存在于核内。然而，其潜在的核功能仍知之甚少。在这里，我们发现参与单核细胞/巨噬细胞生成的集落刺激因子-1 受体 (CSF-1R) 的全长蛋白的一部分在人原代单核细胞受到 CSF-1 刺激时会迁移到核内。染色质免疫沉淀鉴定出 CSF-1R 优先招募到基因间区域，在那里它与 H3K4me1 共定位，并与转录因子 EGR1 相互作用。当单核细胞用 CSF-1 分化为巨噬细胞时，CSF-1R 被重新定向到转录起始位点，与 H3K4me3 共定位，并与 ELK 和 YY1 转录因子相互作用。CSF-1R 的表达和染色质募集受小分子 CSF-1R 抑制剂的调节，并在慢性骨髓单核细胞白血病患者的单核细胞中发生改变。揭示这种动态的非典型 CSF-1R 功能为探索该受体及其配体的功能提供了新的途径。
