The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages
The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages
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DOI：
10.1101/gad.1493506
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发表时间：
2006-11-01
影响因子：
10.5
通讯作者：
Akashi, Koichi
中科院分区：
文献类型：
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作者：
Iwasaki, Hiromi;Mizuno, Shin-ichi;Akashi, Koichi
多能干细胞的谱系分化机制尚未完全清楚。我们最近分离出具有嗜酸性粒细胞、嗜碱性粒细胞或肥大细胞谱系潜力的祖细胞，所有这些祖细胞都来自粒细胞/单核细胞祖细胞(GMP)。通过使用这些预期纯化的前体细胞，我们在这里表明GATA-2和CCAAT增强子结合蛋白α(C/EBPα)的表达时机可以不同地控制它们的谱系承诺。GATA-2的表达指示表达C/EBPα的GMP专一地进入嗜酸性粒细胞谱系，而如果C/EBPα在GMP阶段被抑制，GATA-2则诱导嗜碱性粒细胞和/或肥大细胞谱系的承诺。此外，通过简单地改变C/EBPα和GATA-2转导的顺序，即使是致力于淋巴系的祖细胞也重新获得了这些发育过程，并被重新编程到这些谱系中的每一个。我们认为，关键转录因子的表达顺序对于它们相互作用选择性地驱动谱系指定程序至关重要，通过这些程序，干细胞可以以分层的方式产生多个谱系细胞。
The mechanism of lineage specification in multipotent stem cells has not been fully understood. We recently isolated progenitors with the eosinophil, basophil, or mast cell lineage potential, all of which originate from granulocyte/ monocyte progenitors (GMPs). By using these prospectively purified progenitors, we show here that the expression timing of GATA-2 and CCAAT enhancer-binding protein alpha (C/EBP alpha) can differentially control their lineage commitment. The expression of GATA-2 instructed C/EBP alpha-expressing GMPs to commit exclusively into the eosinophil lineage, while it induced basophil and/or mast cell lineage commitment if C/EBP alpha was suppressed at the GMP stage. Furthermore, simply by switching the order of C/EBP alpha and GATA-2 transduction, even lymphoid-committed progenitors recaptured these developmental processes to be reprogrammed into each of these lineages. We propose that the order of expression of key transcription factors is critical for their interplay to selectively drive lineage specification programs, by which stem cells could generate multiple lineage cells in a hierarchical manner.