Felgner J, Kreipe H, Heidorn K, Jaquet K, Heuss R, Zschunke F, Radzun H J, Parwaresch M R
Institute of Pathology, Kiel, Germany.
Leukemia. 1992 May;6(5):420-5.
DNA methylation belongs to the multilevel genetic control system regulating differentiation processes and gene expression. The extent to which DNA methylation contributes to the differentiation of hematopoietic cells is elusive. In the present study we investigated the methylation state of the c-fms/M-CSF receptor gene in normal human blood cells and tissue macrophages. The methylation pattern of the c-fms gene as detected by isoschizomeric restriction analysis with MspI/HpaII showed only slight interindividual variations in normal donors, whereas constant differences were found between granulocytes and monocytes from the same donor. The second intron of the c-fms gene contains several CpG loci which were found to be hypomethylated on both alleles in monocytes and tissue macrophages. By contrast, these positions were methylated in granulocytes and lymphocytes that did not express the c-fms gene. In comparison to monocytes alveolar and peritoneal macrophages revealed an enhanced demethylation. There were constant differences in c-fms gene methylation between alveolar and peritoneal macrophages with a higher degree of demethylation in alveolar macrophages. We conclude that c-fms gene demethylation is involved in the differentiation of monocytes and macrophages from immature precursors and that the demethylation of lineage-specific growth factor receptor genes might provide an important step in lineage commitment of hematopoietic cells.
DNA甲基化属于调节分化过程和基因表达的多层次遗传控制系统。DNA甲基化对造血细胞分化的贡献程度尚不清楚。在本研究中，我们调查了正常人血细胞和组织巨噬细胞中c-fms/M-CSF受体基因的甲基化状态。用MspI/HpaII进行同裂酶限制性分析检测到的c-fms基因甲基化模式在正常供体中仅显示出轻微的个体间差异，而同一供体的粒细胞和单核细胞之间存在恒定差异。c-fms基因的第二个内含子包含几个CpG位点，在单核细胞和组织巨噬细胞的两个等位基因上均发现这些位点低甲基化。相比之下，这些位置在不表达c-fms基因的粒细胞和淋巴细胞中发生甲基化。与单核细胞相比，肺泡巨噬细胞和腹腔巨噬细胞显示出增强的去甲基化。肺泡巨噬细胞和腹腔巨噬细胞之间的c-fms基因甲基化存在恒定差异，肺泡巨噬细胞的去甲基化程度更高。我们得出结论，c-fms基因去甲基化参与了单核细胞和巨噬细胞从未成熟前体的分化过程，并且谱系特异性生长因子受体基因的去甲基化可能是造血细胞谱系定向分化的重要步骤。
