%0 Journal Article
%T UTX maintains the functional integrity of the murine hematopoietic system by globally regulating aging-associated genes.
%A Sera Y
%A Nakata Y
%A Ueda T
%A Yamasaki N
%A Koide S
%A Kobayashi H
%A Ikeda KI
%A Kobatake K
%A Iwasaki M
%A Oda H
%A Wolff L
%A Kanai A
%A Nagamachi A
%A Inaba T
%A Sotomaru Y
%A Ichinohe T
%A Koizumi M
%A Miyakawa Y
%A Honda ZI
%A Iwama A
%A Suda T
%A Takubo K
%A Honda H
%J Blood
%V 137
%N 7
%D 02 2021 18
%M 33174606
%F 25.476
%R 10.1182/blood.2019001044
%X 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.