UTX maintains the functional integrity of the murine hematopoietic system by globally regulating aging-associated genes

Yasuyuki Sera, Yuichiro Nakata, Takeshi Ueda, Norimasa Yamasaki, Shuhei Koide, Hiroshi Kobayashi, Ken ichiro Ikeda, Kohei Kobatake, Masayuki Iwasaki, Hideaki Oda, Linda Wolff, Akinori Kanai, Akiko Nagamachi, Toshiya Inaba, Yusuke Sotomaru, Tatsuo Ichinohe, Miho Koizumi, Yoshihiko Miyakawa, Zen ichiro Honda, Atsushi IwamaToshio Suda, Keiyo Takubo, Hiroaki Honda

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Epigenetic regulation is essential for the maintenance of the hematopoietic system, and its deregulation is implicated in hematopoietic disorders. In this study, UTX, a demethylase for lysine 27 on histone H3 (H3K27) and a component of COMPASS-like and SWI/SNF complexes, played an essential role in the hematopoietic system by globally regulating aging-associated genes. Utx-deficient (UtxΔ/Δ) mice exhibited myeloid skewing with dysplasia, extramedullary hematopoiesis, impaired hematopoietic reconstituting ability, and increased susceptibility to leukemia, which are the hallmarks of hematopoietic aging. RNA-sequencing (RNA-seq) analysis revealed that Utx deficiency converted the gene expression profiles of young hematopoietic stem-progenitor cells (HSPCs) to those of aged HSPCs. Utx expression in hematopoietic stem cells declined with age, and UtxΔ/Δ HSPCs exhibited increased expression of an aging-associated marker, accumulation of reactive oxygen species, and impaired repair of DNA double-strand breaks. Pathway and chromatin immunoprecipitation analyses coupled with RNA-seq data indicated that UTX contributed to hematopoietic homeostasis mainly by maintaining the expression of genes downregulated with aging via demethylase-dependent and -independent epigenetic programming. Of note, comparison of pathway changes in UtxΔ/Δ HSPCs, aged muscle stem cells, aged fibroblasts, and aged induced neurons showed substantial overlap, strongly suggesting common aging mechanisms among different tissue stem cells. Key Points: • Utx deficiency genetically compromises various metabolic and signaling pathways and phenotypically induces hematopoietic aging. • UTX maintains hematopoietic stem cell function via both demethylase-dependent and -independent epigenetic programming.

Original languageEnglish (US)
Pages (from-to)908-922
Number of pages15
JournalBlood
Volume137
Issue number7
DOIs
StatePublished - Feb 18 2021

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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