Epigenetic control of dendritic cell development and fate determination of common myeloid progenitor by Mysm1
Autor: | Vijayalakshmi Nandakumar, Peter Yates, Lindsey Jones, Si-Yi Chen, Haejung Won, Xue F. Huang, Suzi Sanchez |
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Rok vydání: | 2014 |
Předmět: |
Myeloid
Hematopoiesis and Stem Cells Cellular differentiation Immunology Gene Expression Receptor Macrophage Colony-Stimulating Factor Biology Biochemistry Epigenesis Genetic Histones Histone H2A Deubiquitinase MYSM1 hemic and lymphatic diseases Proto-Oncogene Proteins Endopeptidases medicine Animals Humans Epigenetics Progenitor cell Promoter Regions Genetic Cells Cultured Myeloid Progenitor Cells Mice Knockout Reverse Transcriptase Polymerase Chain Reaction Granulocyte-Macrophage Colony-Stimulating Factor Cell Differentiation hemic and immune systems Dendritic Cells Cell Biology Hematology Dendritic cell Flow Cytometry Cell biology Haematopoiesis HEK293 Cells medicine.anatomical_structure fms-Like Tyrosine Kinase 3 Receptors Granulocyte-Macrophage Colony-Stimulating Factor Fms-Like Tyrosine Kinase 3 Trans-Activators Ubiquitin-Specific Proteases Protein Binding |
Zdroj: | Blood. 124:2647-2656 |
ISSN: | 1528-0020 0006-4971 |
Popis: | 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. |
Databáze: | OpenAIRE |
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