論文

2020年11月10日

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

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

記述言語
掲載種別
研究論文(学術雑誌)
DOI
10.1182/blood.2019001044
出版者・発行元
American Society of Hematology

Epigenetic regulation is essential for the maintenance of the hematopoietic system, and its deregulation is implicated in hematopoietic disorders. Here, we show that UTX, a demethylase for lysine 27 on histone H3 (H3K27) and a component of Compass-like and SWI/SNF complexes, plays 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 HSCs declines 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 (ChIP) analyses coupled with RNA-seq data indicated that UTX contributes to hematopoietic homeostasis mainly by maintaining the expression of genes downregulated with aging, via both demethylase-dependent and -independent epigenetic programming. Of note, comparison of pathway changes in UtxΔ/Δ HSPCs, aged muscle stem cells, aged fibroblasts, and aged iPS-induced neuronal cells showed substantial overlap, strongly suggesting common aging mechanisms among different tissue stem cells.

リンク情報
DOI
https://doi.org/10.1182/blood.2019001044
URL
http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2019001044/1789866/blood.2019001044.pdf
ID情報
  • DOI : 10.1182/blood.2019001044
  • ISSN : 0006-4971
  • eISSN : 1528-0020

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