SWI/SNF Complex Prevents Lineage Reversion and Induces Temporal Patterning in Neural Stem Cells
SWI/SNF Complex Prevents Lineage Reversion and Induces Temporal Patterning in Neural Stem Cells
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DOI：
10.1016/j.cell.2014.01.053
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发表时间：
2014-03-13
期刊：
影响因子：
64.5
通讯作者：
Knoblich, Juergen A.
中科院分区：
文献类型：
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作者：
Eroglu, Elif;Burkard, Thomas R.;Knoblich, Juergen A.
SWI/SNF染色质重塑复合物的成员是人类癌症中最常见的突变基因之一，但目前尚不清楚它们如何抑制肿瘤发生。在这里，我们使用果蝇成神经细胞来证明SWI/SNF组件Osa（ARID 1）通过确保干细胞谱系的正确谱系进展来防止肿瘤发生。我们发现，Osa诱导的转录程序中的过境扩增人口，启动时间模式，限制自我更新，并防止去分化。我们确定的Prdm蛋白哈姆雷特作为这个程序的关键组成部分。哈姆雷特由Osa直接诱导，并通过不同的转录状态调节祖细胞的进展，以限制过渡扩增分裂的数量。我们的数据为SWI/SNF广泛的肿瘤抑制活性提供了一个机制性解释。由于哈姆雷特同源物Evi 1和Prdm 16在癌症中经常发生突变，因此这种机制在人类干细胞谱系中很可能是保守的。
Members of the SWI/SNF chromatin-remodeling complex are among the most frequently mutated genes in human cancer, but how they suppress tumorigenesis is currently unclear. Here, we use Drosophila neuroblasts to demonstrate that the SWI/SNF component Osa (ARID1) prevents tumorigenesis by ensuring correct lineage progression in stem cell lineages. We show that Osa induces a transcriptional program in the transit-amplifying population that initiates temporal patterning, limits self-renewal, and prevents dedifferentiation. We identify the Prdm protein Hamlet as a key component of this program. Hamlet is directly induced by Osa and regulates the progression of progenitors through distinct transcriptional states to limit the number of transit-amplifying divisions. Our data provide a mechanistic explanation for the widespread tumor suppressor activity of SWI/SNF. Because the Hamlet homologs Evi1 and Prdm16 are frequently mutated in cancer, this mechanism could well be conserved in human stem cell lineages.