Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of nonhematopoietic genes

Shuhei Koide, Motohiko Oshima, Keiyo Takubo, Satoshi Yamazaki, Eriko Nitta, Atsunori Saraya, Kazumasa Aoyama, Yuko Kato, Satoru Miyagi, Yaeko Nakajima-Takagi, Tetsuhiro Chiba, Hirotaka Matsui, Fumio Arai, Yutaka Suzuki, Hiroshi Kimura, Hiromitsu Nakauchi, Toshio Suda, Yoichi Shinkai, Atsushi Iwama

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)638-649
Number of pages12
JournalBlood
Volume128
Issue number5
DOIs
Publication statusPublished - Aug 4 2016

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Koide, S., Oshima, M., Takubo, K., Yamazaki, S., Nitta, E., Saraya, A., ... Iwama, A. (2016). Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of nonhematopoietic genes. Blood, 128(5), 638-649. https://doi.org/10.1182/blood-2016-01-694810