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
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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