Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of nonhematopoietic genes.
Setdb1, also known as Eset, is a methyltransferase that catalyzes trimethylation of H3K9 (H3K9me3) and plays an essential role in the silencing of endogenous retroviral elements (ERVs) in the developing embryo and embryonic stem cells (ESCs). Its role in somatic stem cells, however, remains unclear because of the early death of Setdb1-deficient embryos. We demonstrate here that Setdb1 is the first H3K9 methyltransferase shown to be essential for the maintenance of hematopoietic stem and progenitor cells (HSPCs) in mice. The deletion of Setdb1 caused the rapid depletion of hematopoietic stem and progenitor cells (HSPCs), as well as leukemic stem cells. In contrast to ESCs, ERVs were largely repressed in Setdb1-deficient HSPCs. A list of nonhematopoietic genes was instead ectopically activated in HSPCs after reductions in H3K9me3 levels, including key gluconeogenic enzyme genes fructose-1,6-bisphosphatase 1 (Fbp1) and Fbp2 The ectopic activation of gluconeogenic enzymes antagonized glycolysis and impaired ATP production, resulting in a compromised repopulating capacity of HSPCs. Our results demonstrate that Setdb1 maintains HSPCs by restricting the ectopic activation of nonhematopoietic genes detrimental to their function and uncover that the gluconeogenic pathway is one of the critical targets of Setdb1 in HSPCs.
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
Shuhei
S
Koide
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
Motohiko
M
Oshima
Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan;
Keiyo
K
Takubo
Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan;
Satoshi
S
Yamazaki
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
Eriko
E
Nitta
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
Atsunori
A
Saraya
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
Kazumasa
K
Aoyama
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
Yuko
Y
Kato
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
Satoru
S
Miyagi
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
Yaeko
Y
Nakajima-Takagi
Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan;
Tetsuhiro
T
Chiba
Department of Molecular Laboratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan;
Hirotaka
H
Matsui
Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
Fumio
F
Arai
Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan;
Yutaka
Y
Suzuki
Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan;
Hiroshi
H
Kimura
Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA;
Hiromitsu
H
Nakauchi
Cancer Science Institute, National University of Singapore, Singapore, Singapore; International Research Center for Medical Sciences, Kumamoto University, Kumamoto City, Japan; and.
Toshio
T
Suda
Cellular Memory Laboratory, RIKEN, Wako, Japan.
Yoichi
Y
Shinkai
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
Atsushi
A
Iwama
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D020077:Endogenous Retroviruses / Q000378:metabolism; D000071858:Epithelial Cell Adhesion Molecule / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005943:Gluconeogenesis / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D007938:Leukemia / Q000235:genetics / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology
D000071858:Epithelial Cell Adhesion Molecule; D011495:Histone-Lysine N-Methyltransferase; C516239:SETDB1 protein, mouse