Bmi1 is critical to prevent Ikaros-mediated lymphoid priming in hematopoietic stem cells

Cell Cycle. 2012 Jan 1;11(1):65-78. doi: 10.4161/cc.11.1.18097. Epub 2012 Jan 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Lineage
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Histones / metabolism
  • Ikaros Transcription Factor / metabolism*
  • Lymphocytes / cytology
  • Lymphocytes / immunology
  • Lymphocytes / metabolism*
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Polycomb Repressive Complex 1
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Repressor Proteins / deficiency
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Transcriptional Activation
  • Ubiquitination

Substances

  • Bmi1 protein, mouse
  • Histones
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • Ikaros Transcription Factor
  • Polycomb Repressive Complex 1