Forced expression of the histone demethylase Fbxl10 maintains self-renewing hematopoietic stem cells.
Exp Hematol, 2011/6;39(6):697-709.e5.
Konuma T[1], Nakamura S, Miyagi S, Negishi M, Chiba T, Oguro H, Yuan J, Mochizuki-Kashio M, Ichikawa H, Miyoshi H, Vidal M, Iwama A
Affiliations
PMID: 21540074DOI: 10.1016/j.exphem.2011.03.008
Impact factor: 3.249
Abstract
objective: The methylation status of histones changes dramatically depending on cellular context and defines cell type-specific gene expression profiles. Histone demethylases have recently been implicated in this process. However, it is unknown how histone demethylases function in the maintenance of self-renewing hematopoietic stem cells (HSCs).
materials and methods: We profiled the expression of histone demethylase genes in mouse hematopoietic cells and listed genes preferentially expressed in HSCs. We analyzed the impact of a selected gene by transducing CD34(-)c-Kit(+)Sca-1(+)lineage marker(-) (CD34(-)KSL) HSCs using retroviral system followed by in vitro methylcellulose colony assays and in vivo competitive repopulation assays.
results: We found that F-box and leucine-rich repeat protein 10 (Fbxl10, also known as Jhdm1b or Kdm2b), is highly expressed in CD34(-)KSL HSCs. Fbxl10 encodes a demethylase specific to the histone H3 mono/di-methylated at lysine 36 (H3K36me1/me2) and forms complexes with polycomb-group proteins, essential regulators of HSCs. Forced expression of Fbxl10 in HSCs expanded numbers of colony-forming cells with multilineage differentiation potential in culture and prevented exhaustion of the long-term repopulating potential of HSCs following serial transplantation. Fbxl10 tightly repressed the expression of cyclin-dependent kinase inhibitor genes, including Ink4a, Ink4b, and Ink4c, through direct binding to their promoters and gene bodies and demethylation at H3K36. Increased levels of mono-ubiquitylation of H2A at target loci also suggested the collaboration of Fbxl10 with polycomb-group proteins.
conclusions: Our findings implicate Fbxl10 in the maintenance of self-renewal capacity of HSCs, thus highlight a role of histone demethylation for the first time in the epigenetic regulation of HSCs.
MeSH terms
Animals; Chromatin Immunoprecipitation; Cyclin-Dependent Kinases; F-Box Proteins; Gene Expression Profiling; Hematopoietic Stem Cells; Jumonji Domain-Containing Histone Demethylases; Mice; Mice, Inbred C57BL; Reverse Transcriptase Polymerase Chain Reaction; Transcription, Genetic
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