Follows George A, Tagoh Hiromi, Lefevre Pascal, Morgan Gareth J, Bonifer Constanze
Molecular Medicine Unit, University of Leeds, St James's University Hospital, Leeds LS9 7TF, UK.
Nucleic Acids Res. 2003 Oct 15;31(20):5805-16. doi: 10.1093/nar/gkg804.
The c-FMS gene encodes the macrophage colony-stimulating factor receptor (M-CSFR or CSF1-R), which is a tyrosine kinase growth factor receptor essential for macrophage development. We have previously characterized the chromatin features of the mouse gene; however, very little is known about chromatin structure and function of the human c-FMS locus. Here we present a side-by-side comparison of the chromatin structure, histone modification, transcription factor occupancy and cofactor recruitment of the human and the mouse c-FMS loci. We show that, similar to the mouse gene, the human c-FMS gene possesses a promoter and an intronic enhancer element (c-fms intronic regulatory element or FIRE). Both elements are evolutionarily conserved and specifically active in macrophages. However, we demonstrate by in vivo footprinting that both murine and human c-FMS cis-regulatory elements are recognised by an overlapping, but non-identical, set of transcription factors. Despite these differences, chromatin immunoprecipitation experiments show highly similar patterns of histone H3 modification and a similar distribution of chromatin modifying and remodelling activities at individual cis-regulatory elements and across the c-FMS locus. Our experiments support the hypothesis that the same regulatory principles operate at both genes via conserved cores of transcription factor binding sites.
c-FMS基因编码巨噬细胞集落刺激因子受体（M-CSFR或CSF1-R），它是一种酪氨酸激酶生长因子受体，对巨噬细胞发育至关重要。我们之前已对小鼠基因的染色质特征进行了表征；然而，关于人类c-FMS基因座的染色质结构和功能却知之甚少。在此，我们对人类和小鼠c-FMS基因座的染色质结构、组蛋白修饰、转录因子占据情况及辅因子募集进行了并列比较。我们发现，与小鼠基因类似，人类c-FMS基因拥有一个启动子和一个内含子增强子元件（c-fms内含子调控元件或FIRE）。这两个元件在进化上保守且在巨噬细胞中具有特异性活性。然而，我们通过体内足迹法证明，小鼠和人类的c-FMS顺式调控元件被一组重叠但不完全相同的转录因子识别。尽管存在这些差异，但染色质免疫沉淀实验显示，组蛋白H3修饰模式高度相似，且在各个顺式调控元件以及整个c-FMS基因座上，染色质修饰和重塑活性的分布也相似。我们的实验支持这样一种假设，即相同的调控原则通过转录因子结合位点的保守核心在两个基因上发挥作用。
