title: Bmi1 is critical to prevent Ikaros-mediated lymphoid priming in hematopoietic stem cells.
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.
authors.affiliation: Stem Cell Aging Group, Spanish National Cardiovascular Research Center, Madrid, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Arranz
authors.forename: Antonio
authors.initials: A
authors.lastname: Herrera-Merchan
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Ligos
authors.forename: Antonio
authors.initials: A
authors.lastname: de Molina
authors.forename: Orlando
authors.initials: O
authors.lastname: Dominguez
authors.forename: Susana
authors.initials: S
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D051740:Ikaros Transcription Factor / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D054875:Ubiquitination
chemical_list: C489421:Bmi1 protein, mouse; D006657:Histones; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D051740:Ikaros Transcription Factor; D063150:Polycomb Repressive Complex 1