Human Disease Models, Institute of Laboratory Animals, Tokyo Women's Medical University, Tokyo, Japan.
Chromatin Dynamics in Stem Cells and Cancer Laboratory, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL.
Blood. 2021 Feb 18;137(7):908-922. doi: 10.1182/blood.2019001044.
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.
表观遗传调控对于维持造血系统至关重要，其失调与造血紊乱有关。在这项研究中，UTX 是组蛋白 H3 赖氨酸 27 的去甲基酶（H3K27），也是 COMPASS 样和 SWI/SNF 复合物的组成部分，通过全局调控与衰老相关的基因，在造血系统中发挥着重要作用。Utx 缺失（UtxΔ/Δ）小鼠表现出骨髓偏向性发育不良、骨髓外造血、造血重建能力受损和对白血病易感性增加，这些都是造血衰老的特征。RNA 测序（RNA-seq）分析显示，Utx 缺失将年轻造血干祖细胞（HSPCs）的基因表达谱转化为年老 HSPCs 的基因表达谱。造血干细胞中的 Utx 表达随年龄增长而下降，而 UtxΔ/Δ HSPCs 表现出衰老相关标志物表达增加、活性氧积累和 DNA 双链断裂修复受损。结合 RNA-seq 数据的通路和染色质免疫沉淀分析表明，UTX 主要通过去甲基酶依赖和非依赖的表观遗传编程来维持与衰老相关的基因表达下调，从而有助于造血稳态。值得注意的是，UtxΔ/Δ HSPCs、衰老肌肉干细胞、衰老成纤维细胞和衰老诱导神经元中通路变化的比较显示出大量重叠，强烈表明不同组织干细胞之间存在共同的衰老机制。
