IWASAKI Masayuki
   Department   Research Institutes and Facilities, Research Institutes and Facilities
   Position   Assistant Professor
Article types Original article
Language English
Peer review Peer reviewed
Title UTX maintains the functional integrity of the murine hematopoietic system by globally regulating aging-associated genes.
Journal Formal name:Blood
ISSN code:15280020/00064971
Domestic / ForeginForegin
Volume, Issue, Page 137(7),pp.908-922
Author and coauthor Sera Yasuyuki†, Nakata yuichiro, Ueda Takeshi, Yamasaki norimasa, Koide shuhei, Kobayashi hiroshi, Ikeda kenichiro, Kobatake Kohei, Iwasaki Masayuki, Oda Hideaki, Wolff Linda, Kanai Akinori, Nagamachi Akiko, Inaba Toshiya, Sotomaru Yusuke, Ichinohe Tatsuo, Koizumi Miho, Miyakawa Yoshihiko, Honda Zenichiro, Iwama Atsushi, Suda Toshio, Takubo Keiyo, Honda Hiroaki
Publication date 2021/02
Summary 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.
DOI 10.1182/blood.2019001044
PMID 33174606