Przybilla Jens, Rohlf Thimo, Loeffler Markus, Galle Joerg
Interdisciplinary Center for Bioinformatics, University Leipzig, Haertelstr. 16-18, 04107, Leipzig, Germany.
Aging Cell. 2014 Apr;13(2):320-8. doi: 10.1111/acel.12177. Epub 2014 Jan 15.
During aging, a decline in stem cell function is observed in many tissues. This decline is accompanied by complex changes of the chromatin structure among them changes in histone modifications and DNA methylation which both affect transcription of a tissue-specific subset of genes. A mechanistic understanding of these age-associated processes, their interrelations and environmental dependence is currently lacking. Here, we discuss related questions on the molecular, cellular, and population level. We combine an individual cell-based model of stem cell populations with a model of epigenetic regulation of transcription. The novel model enables to simulate age-related changes of trimethylation of lysine 4 at histone H3 and of DNA methylation. These changes entail expression changes of genes that induce age-related phenotypes (ARPs) of cells. We compare age-related changes of regulatory states in quiescent stem cells occupying a niche with those observed in proliferating cells. Moreover, we analyze the impact of the activity of the involved epigenetic modifiers on these changes. We find that epigenetic aging strongly affects stem cell heterogeneity and that homing at stem cell niches retards epigenetic aging. Our model provides a mechanistic explanation how increased stem cell proliferation can lead to progeroid phenotypes. Adapting our model to properties observed for aged hematopoietic stem cell (HSC) clones, we predict that the hematopoietic ARP activates young HSCs and thereby retards aging of the entire HSC population. In addition, our model suggests that the experimentally observed high interindividual variance in HSC numbers originates in a variance of histone methyltransferase activity.
在衰老过程中，许多组织中都观察到干细胞功能下降。这种下降伴随着染色质结构的复杂变化，其中包括组蛋白修饰和DNA甲基化的变化，这两者都会影响组织特异性基因子集的转录。目前尚缺乏对这些与年龄相关的过程及其相互关系和环境依赖性的机制理解。在这里，我们在分子、细胞和群体水平上讨论相关问题。我们将基于单个细胞的干细胞群体模型与转录的表观遗传调控模型相结合。这个新模型能够模拟组蛋白H3赖氨酸4三甲基化和DNA甲基化与年龄相关的变化。这些变化导致诱导细胞年龄相关表型（ARP）的基因表达变化。我们比较了占据生态位的静止干细胞与增殖细胞中调控状态的年龄相关变化。此外，我们分析了相关表观遗传修饰因子的活性对这些变化的影响。我们发现表观遗传衰老强烈影响干细胞的异质性，并且干细胞归巢到生态位会延缓表观遗传衰老。我们的模型提供了一个机制解释，即增加的干细胞增殖如何导致早衰表型。将我们的模型应用于老年造血干细胞（HSC）克隆所观察到的特性，我们预测造血ARP会激活年轻的HSC，从而延缓整个HSC群体的衰老。此外，我们的模型表明，实验观察到的HSC数量的高个体间差异源于组蛋白甲基转移酶活性的差异。
