Bmi1 is critical to prevent Ikaros-mediated lymphoid priming in hematopoietic stem cells.
Cell Cycle, 2012/1/01;11(1):65-78.
Arranz L[1], Herrera-Merchan A, Ligos JM, de Molina A, Dominguez O, Gonzalez S
Affiliations
PMID: 22185780DOI: 10.4161/cc.11.1.18097
Impact factor: 5.173
Abstract
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.
MeSH terms
Animals; Cell Differentiation; Cell Lineage; Hematopoietic Stem Cells; Histones; Ikaros Transcription Factor; Lymphocytes; Mice; Mice, Knockout; Nuclear Proteins; Polycomb Repressive Complex 1; Proto-Oncogene Proteins; Repressor Proteins; Transcriptional Activation; Ubiquitination
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