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望月 牧子
Department School of Medicine, School of Medicine Position Assistant Professor |
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| Article types | Original article |
| Language | English |
| Peer review | Peer reviewed |
| Title | Forced expression of the histone demethylase Fbxl10 maintains self-renewing hematopoietic stem cells. |
| Journal | Formal name：Experimental hematology Abbreviation：Exp Hematol ISSN code：18732399/0301472X |
| Domestic / Foregin | Foregin |
| Volume, Issue, Page | 39(6),pp.697-709.e5 |
| Author and coauthor | Konuma Takaaki, Nakamura Shunsuke, Miyagi Satoru, Negishi Masamitsu, Chiba Tetsuhiro, Oguro Hideyuki, Yuan Jin, Mochizuki-Kashio Makiko, Ichikawa Hitoshi, Miyoshi Hiroyuki, Vidal Miguel, Iwama Atsushi |
| Publication date | 2011/06 |
| Summary | 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. |
| DOI | 10.1016/j.exphem.2011.03.008 |
| PMID | 21540074 |