异染色质
生物
DNA甲基化
内源性逆转录病毒
祖细胞
表观遗传学
造血
细胞生物学
异染色质蛋白1
干细胞
遗传学
染色质
DNA
基因表达
基因
基因组
作者
Tingting Hong,Jia Li,Lei Guo,Maryn Cavalier,Tianlu Wang,Dou Yu,Aaron DeLaFuente,Shaohai Fang,Anna Guzman,Katharina Wohlan,Chiraag Kapadia,Carina Rosas,Ya‐Ling Yang,C. Cameron Yin,Shaoying Li,M. James You,Xiaodong Cheng,Margaret A. Goodell,Yubin Zhou,Yun Huang
出处
期刊:Nature Aging
日期:2023-10-26
卷期号:3 (11): 1387-1400
被引量:5
标识
DOI:10.1038/s43587-023-00505-y
摘要
DNA methylation deregulation at partially methylated domains (PMDs) represents an epigenetic signature of aging and cancer, yet the underlying molecular basis and resulting biological consequences remain unresolved. We report herein a mechanistic link between disrupted DNA methylation at PMDs and the spatial relocalization of H3K9me3-marked heterochromatin in aged hematopoietic stem and progenitor cells (HSPCs) or those with impaired DNA methylation. We uncover that TET2 modulates the spatial redistribution of H3K9me3-marked heterochromatin to mediate the upregulation of endogenous retroviruses (ERVs) and interferon-stimulated genes (ISGs), hence contributing to functional decline of aged HSPCs. TET2-deficient HSPCs retain perinuclear distribution of heterochromatin and exhibit age-related clonal expansion. Reverse transcriptase inhibitors suppress ERVs and ISGs expression, thereby restoring age-related defects in aged HSPCs. Collectively, our findings deepen the understanding of the functional interplay between DNA methylation and histone modifications, which is vital for maintaining heterochromatin function and safeguarding genome stability in stem cells. Hong, Li and colleagues unveil a pivotal role of TET2 in heterochromatin relocalization, aberrant upregulation of endogenous retroviruses and overactivated innate immune response in hematopoietic stem and progenitor cells during aging.
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