UTX maintains the functional integrity of the murine hematopoietic system by globally regulating aging-associated genes
| Autor: | Kenichiro Ikeda, Hideaki Oda, Miho Koizumi, Toshiya Inaba, Akiko Nagamachi, Kohei Kobatake, Takeshi Ueda, Hiroshi Kobayashi, Zen-ichiro Honda, Keiyo Takubo, Linda Wolff, Yusuke Sotomaru, Toshio Suda, Tatsuo Ichinohe, Masayuki Iwasaki, Yasuyuki Sera, Yuichiro Nakata, Atsushi Iwama, Shuhei Koide, Akinori Kanai, Hiroaki Honda, Norimasa Yamasaki, Yoshihiko Miyakawa |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Aging Jumonji Domain-Containing Histone Demethylases Myeloid DNA Repair Hematopoiesis and Stem Cells Hematopoietic System Virus Integration Immunology Biology Biochemistry 03 medical and health sciences Histone H3 Mice 0302 clinical medicine Immune Reconstitution medicine Animals DNA Breaks Double-Stranded Genetic Predisposition to Disease Myeloid Cells Epigenetics Cellular Senescence Histone Demethylases Mice Knockout Leukemia Experimental Cell Biology Hematology Recombinant Proteins Cell biology Hematopoiesis Gene expression profiling Histone Code Haematopoiesis 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation 030220 oncology & carcinogenesis Hematopoiesis Extramedullary Radiation Chimera biology.protein Demethylase Female Stem cell Moloney murine leukemia virus Reactive Oxygen Species Chromatin immunoprecipitation Transcription Factors |
| Zdroj: | Blood |
| ISSN: | 1528-0020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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