Proliferation-Dependent Alterations of the DNA Methylation Landscape Underlie Hematopoietic Stem Cell Aging
Proliferation-Dependent Alterations of the DNA Methylation Landscape Underlie Hematopoietic Stem Cell Aging
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DOI：
10.1016/j.stem.2013.01.017
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发表时间：
2013-04-04
期刊：
影响因子：
23.9
通讯作者：
Rossi, Derrick J.
中科院分区：
文献类型：
--
作者：
Beerman, Isabel;Bock, Christoph;Rossi, Derrick J.
造血干细胞（HSC）的功能潜力在衰老过程中下降，并且在这样做的过程中，显着有助于老年人的造血病理生理学。为了探索年龄相关的HSC衰退与表观基因组之间的关系，我们结合功能分析检测了个体发育过程中HSC的整体DNA甲基化。虽然DNA甲基化组在衰老过程中通常是稳定的，但DNA甲基化的位点特异性改变发生在与造血谱系潜力相关的基因组区域，并选择性靶向下游祖细胞和效应细胞中表达的基因。我们发现，与年龄相关的HSC衰退、复制限制和DNA甲基化在很大程度上依赖于HSC的增殖历史，但似乎与端粒长度无关。生理老化和实验性HSC增殖均导致多梳抑制复合物2调控的基因DNA超甲基化。我们的研究结果提供了证据表明，DNA甲基化景观的表观基因组改变有助于衰老过程中HSC的功能下降。
The functional potential of hematopoietic stem cells (HSCs) declines during aging, and in doing so, significantly contributes to hematopoietic pathophysiology in the elderly. To explore the relationship between age-associated HSC decline and the epigenome, we examined global DNA methylation of HSCs during ontogeny in combination with functional analysis. Although the DNA methylome is generally stable during aging, site-specific alterations of DNA methylation occur at genomic regions associated with hematopoietic lineage potential and selectively target genes expressed in downstream progenitor and effector cells. We found that age-associated HSC decline, replicative limits, and DNA methylation are largely dependent on the proliferative history of HSCs, yet appear to be telomere-length independent. Physiological aging and experimentally enforced proliferation of HSCs both led to DNA hypermethylation of genes regulated by Polycomb Repressive Complex 2. Our results provide evidence that epigenomic alterations of the DNA methylation landscape contribute to the functional decline of HSCs during aging.