Epigenetic control of dendritic cell development and fate determination of common myeloid progenitor by Mysm1

• Published in: Blood 2014-10, Vol.124 (17), p.2647-2656
• Main Authors: Won, Haejung, Nandakumar, Vijayalakshmi, Yates, Peter, Sanchez, Suzi, Jones, Lindsey, Huang, Xue F., Chen, Si-Yi
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cells, Cultured; Dendritic Cells - metabolism; Endopeptidases - genetics; Endopeptidases - metabolism; Epigenesis, Genetic; Flow Cytometry; fms-Like Tyrosine Kinase 3 - genetics; fms-Like Tyrosine Kinase 3 - metabolism; Gene Expression; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; HEK293 Cells; Hematopoiesis and Stem Cells; Histones - metabolism; Humans; Mice, Knockout; Myeloid Progenitor Cells - metabolism; Promoter Regions, Genetic - genetics; Protein Binding; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Receptor, Macrophage Colony-Stimulating Factor - genetics; Receptor, Macrophage Colony-Stimulating Factor - metabolism; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Trans-Activators - genetics; Trans-Activators - metabolism; Ubiquitin-Specific Proteases
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-10-534313

The mechanisms controlling the development of dendritic cells (DCs) remain incompletely understood. Using an Mysm1 knockout (Mysm1−/−) mouse model, we identified the histone H2A deubiquitinase Mysm1, as a critical regulator in DC differentiation. Mysm1−/− mice showed a global reduction of DCs in lymphoid organs, whereas development of granulocytes and macrophages were not severely affected. Hematopoietic progenitors and DC precursors were significantly decreased in Mysm1−/− mice and defective in Fms-like tyrosine kinase-3(Flt3) ligand–induced, but not in granulocyte macrophage–colony-stimulating factor (GM-CSF)-induced DC differentiation in vitro. Molecular studies demonstrated that the developmental defect of DCs from common myeloid progenitor (CMP) in Mysm1−/− mice is associated with decreased Flt3 expression and that Mysm1 derepresses transcription of the Flt3 gene by directing histone modifications at the Flt3 promoter region. Two molecular mechanisms were found to be responsible for the selective role of Mysm1 in lineage determination of DCs from CMPs: the selective expression of Mysm1 in a subset of CMPs and the different requirement of Mysm1 for PU.1 recruitment to the Flt3 locus vs GM-CSF-α and macrophage–colony-stimulating factor receptor loci. In conclusion, this study reveals an essential role of Mysm1 in epigenetic regulation of Flt3 transcription and DC development, and it provides a novel mechanism for lineage determination from CMP. •Deletion of Mysm1 impairs development of steady-state DC, but no other myeloid lineages; monocyte, macrophage, and granulocyte.•Mysm1 governs DC differentiation from CMP by regulating Flt3 expression via modulating histone modifications and mediating Pu.1 recruitment.