RRC ID 61622
Author Sera Y, Nakata Y, Ueda T, Yamasaki N, Koide S, Kobayashi H, Ikeda KI, Kobatake K, Iwasaki M, Oda H, Wolff L, Kanai A, Nagamachi A, Inaba T, Sotomaru Y, Ichinohe T, Koizumi M, Miyakawa Y, Honda ZI, Iwama A, Suda T, Takubo K, Honda H.
Title UTX maintains the functional integrity of the murine hematopoietic system by globally regulating aging-associated genes.
Journal Blood
Abstract 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.
Volume 137(7)
Pages 908-922
Published 2021-2-18
DOI 10.1182/blood.2019001044
PII S0006-4971(21)00312-8
PMID 33174606
PMC PMC7918186
MeSH Aging / genetics* Animals Cellular Senescence / genetics DNA Breaks, Double-Stranded DNA Repair Female Gene Expression Regulation / genetics* Genetic Predisposition to Disease Hematopoiesis / genetics* Hematopoiesis, Extramedullary Hematopoietic System / physiology* Histone Code / genetics* Histone Demethylases / deficiency Histone Demethylases / genetics Histone Demethylases / physiology* Immune Reconstitution Jumonji Domain-Containing Histone Demethylases / metabolism Leukemia, Experimental / genetics Leukemia, Experimental / virology Male Mice Mice, Knockout Moloney murine leukemia virus / physiology Myeloid Cells / pathology Radiation Chimera Reactive Oxygen Species / metabolism Recombinant Proteins / metabolism Transcription Factors / metabolism Virus Integration
IF 17.794
Mice RBRC01834