Bmi1 is critical to prevent Ikaros-mediated lymphoid priming in hematopoietic stem cells
Volume 11, Issue 1
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January 1, 2012
Pages 65 - 78http://dx.doi.org/10.4161/cc.11.1.18097
Authors: Lorena Arranz, Antonio Herrera-Merchan, Jose Manuel Ligos, Antonio de Molina, Orlando Dominguez and Susana Gonzalez View affiliations
Preservation of hematopoietic hierarchy requires a constant and reciprocal interplay between chromatin-specific epigenetic regulators and lineage-modifying transcription factors. The polycomb member Bmi1 is a key factor in hematopoietic stem cell (HSC) maintenance, but its specific physiological role in subsequent hematopoietic lineage-specific commitments is unclear. Here, we generated conditional Bmi1 knockout (Bmi1-KO) mice. Selective ablation of Bmi1 in the hematopoietic system induced extensive upregulation of Ikaros and concomitant Ikaros-dependent lymphoid-lineage transcriptional priming, which is marked by their loss of H2A ubiquitination and increased H3K4 trimethylation in Bmi1-KO long-term HSCs (LT-HSCs). Removal of Ikaros in Bmi1-null LT-HSCs significantly diminished the hematopoietic defects seen in conditional Bmi1-KO mice. These alterations resulted in recovering the Bmi1-KO exhausted quiescent stem-cell pool, whereas the block in Bmi1-KO lymphoid-progenitor differentiation was rescued, allowing the development of mature lymphoid cells. Together, our results indicate that Ikaros is a critical Bmi1 target in vivo that prevents premature lineage specification of HSCs.
Received: September 7, 2011; Accepted: September 14, 2011