TY - JOUR
T1 - Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of nonhematopoietic genes
AU - Koide, Shuhei
AU - Oshima, Motohiko
AU - Takubo, Keiyo
AU - Yamazaki, Satoshi
AU - Nitta, Eriko
AU - Saraya, Atsunori
AU - Aoyama, Kazumasa
AU - Kato, Yuko
AU - Miyagi, Satoru
AU - Nakajima-Takagi, Yaeko
AU - Chiba, Tetsuhiro
AU - Matsui, Hirotaka
AU - Arai, Fumio
AU - Suzuki, Yutaka
AU - Kimura, Hiroshi
AU - Nakauchi, Hiromitsu
AU - Suda, Toshio
AU - Shinkai, Yoichi
AU - Iwama, Atsushi
N1 - Publisher Copyright:
© 2016 by The American Society of Hematology.
PY - 2016/8/4
Y1 - 2016/8/4
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2016-01-694810
DO - 10.1182/blood-2016-01-694810
M3 - Article
C2 - 27301860
AN - SCOPUS:85016445512
VL - 128
SP - 638
EP - 649
JO - Blood
JF - Blood
SN - 0006-4971
IS - 5
ER -