The transcriptional program of terminal granulocytic differentiation
The transcriptional program of terminal granulocytic differentiation
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DOI：
10.1182/blood-2004-08-3346
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发表时间：
2005-02-15
期刊：
影响因子：
20.3
通讯作者：
Borregaard, N
中科院分区：
文献类型：
--
作者：
Theilgaard-Mönch, K;Jacobsen, LC;Borregaard, N
为了描述体内控制终端粒细胞分化的转录程序，我们对高富集早幼粒细胞（PMs）、髓细胞/变髓细胞（MYs）和中性粒细胞（bm- pmn）的人骨髓群体进行了全面的微阵列分析。这些分析确定了11310个参与分化的基因，其中6700个受到差异调节，包括以前未识别的效应蛋白和中性粒细胞的表面受体。PMs向MYs的分化伴随着增殖和一般细胞活性的显著下降，这是通过E2启动子结合因子（E2F）靶基因的下调来定义的；细胞周期蛋白依赖性激酶2、4和6；以及各种代谢，蛋白酶体和线粒体基因。凋亡基因的表达模式表明pmms中的p53途径和bm-PMNs中的死亡受体途径控制死亡。对宿主防御至关重要的效应蛋白在粒细胞分化过程中陆续表达，而激活宿主防御程序所必需的受体和受体配体在bm-PMNs中最终上调。核因子- kappab （NF-kappaB）的诱导剂和靶基因配体-受体对的上调表明，NF-kappaB在bm-PMNs中通过自分泌环构成性激活。总的来说，这些结果定义了一个由高度协调的故障安全程序控制的粒细胞分化模型，该模型在细胞获得对伴随感染的激活刺激的反应性之前促进了分化的完成。(C) 2005年由美国血液病学会出版。
To characterize the transcriptional program that governs terminal granulocytic differentiation in vivo, we performed comprehensive microarray analyses of human bone marrow populations highly enriched in promyelocytes (PMs), myelocytes/ metamyelocytes (MYs), and neutrophils (bm-PMNs). These analyses identified 11 310 genes involved in differentiation, of which 6700 were differentially regulated, including previously unidentified effector proteins and surface receptors of neutrophils. Differentiation of PMs toward MYs was accompanied by a marked decline of proliferative and general cellular activity as defined by down-regulation of E2 promoter binding factor (E2F) target genes; cyclin dependent kinases 2,4, and 6; and various metabolic, proteasomal, and mitochondrial genes. Expression patterns of apoptosis genes indicated death control by the p53 pathway in PMs and by death receptor pathways in bm-PMNs. Effector proteins critical for host defense were expressed successively throughout granulocytic differentiation, whereas receptors and receptor ligands essential for the activation of the host defense program were terminally up-regulated in bm-PMNs. The up-regulation of ligand- receptor pairs, which are defined inducers as well as target genes of nuclear factor-kappaB (NF-kappaB), suggests a constitutive activation of NF-kappaB in bm-PMNs by autocrine loops. Overall, these results define a granulocytic differentiation model governed by a highly coordinated failsafe program, which promotes completion of differentiation before cells gain responsiveness toward activating stimuli that accompany infections. (C) 2005 by The American Society of Hematology.