Multilineage transcriptional priming and determination of alternate hematopoietic cell fates
Multilineage transcriptional priming and determination of alternate hematopoietic cell fates
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DOI：
10.1016/j.cell.2006.06.052
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发表时间：
2006-08-25
期刊：
影响因子：
64.5
通讯作者：
Singh, Harinder
中科院分区：
文献类型：
--
作者：
Laslo, Peter;Spooner, Chauncey J.;Singh, Harinder
造血干细胞及其祖细胞呈现多谱系基因表达模式。由于缺乏合适的实验系统，在细胞命运决定过程中这些模式产生和细化的分子机制仍未被探索。利用PU.1（-/-）祖细胞，我们证明在亚阈值水平，这种Ets转录因子在单个髓系祖细胞内调节一种混合的（巨噬细胞/中性粒细胞）基因表达模式。PU.1水平升高会细化该模式，并通过调节一个由反向拮抗抑制因子Egr - 1、2/Nab2和Gfi - 1组成的新型调控回路来促进巨噬细胞分化。Egr - 1和Egr - 2具有冗余功能，可激活巨噬细胞基因并抑制中性粒细胞程序。这些结果被用于构建一个基因调控网络并进行数学建模，该网络表现出分级和双稳态行为，并解释了细胞命运决定过程中混合谱系模式的起始和解决。
Hematopoietic stem cells and their progenitors exhibit multilineage patterns of gene expression. Molecular mechanisms underlying the generation and refinement of these patterns during cell fate determination remain unexplored because of the absence of suitable experimental systems. Using PU.1(-/-) progenitors, we demonstrate that at subthreshold levels, this Ets transcription factor regulates a mixed pattern (macrophage/neutrophil) of gene expression within individual myeloid progenitors. Increased PU.1 levels refine the pattern and promote macrophage differentiation by modulating a novel regulatory circuit comprised of counter antagonistic repressors, Egr-1,2/Nab2 and Gfi-1. Egr-1 and Egr-2 function redundantly to activate macrophage genes and to repress the neutrophil program. These results are used to assemble and mathematically model a gene regulatory network that exhibits both graded and bistable behaviors and accounts for the onset and resolution of mixed lineage patterns during cell fate determination.