Journal
CELL
Volume 156, Issue 6, Pages 1259-1273Publisher
CELL PRESS
DOI: 10.1016/j.cell.2014.01.053
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Funding
- Austrian Academy of Sciences
- Austrian Science Fund (FWF) [I_552-B19, I_1281_B19, Z_153_B09]
- European Research Council
- Austrian Science Fund (FWF) [Z 153, I 1281] Funding Source: researchfish
- Austrian Science Fund (FWF) [Z153] Funding Source: Austrian Science Fund (FWF)
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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.
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