Age-related memory impairment is associated with disrupted multivariate epigenetic coordination in the hippocampus.
Age-related memory impairment is associated with disrupted multivariate epigenetic coordination in the hippocampus.
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DOI：
10.1371/journal.pone.0033249
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Rapp PR
中科院分区：
文献类型：
--
作者：
Castellano JF;Fletcher BR;Kelley-Bell B;Kim DH;Gallagher M;Rapp PR
越来越多的证据将表观遗传调控与记忆相关的突触可塑性联系起来，这提出了染色质修饰动力学改变可能导致年龄依赖性认知能力下降的可能性。在这里，我们表明，在年轻成年海马体中观察到的基线和经验依赖的表观遗传调控的协调编排随着认知衰老而丧失。使用一个充分表征的大鼠模型，可以可靠地区分具有显着记忆障碍的老年个体和记忆正常的个体，没有任何单一的表观遗传标记或海马体中的经验依赖性修饰能够唯一预测衰老认知结果的差异。相反，结果指出了一种多变量模式，其中修饰特异性的双向染色质调节取决于最近的行为经验、实际年龄、认知状态和海马区域。尽管许多表观遗传特征与认知功能保留的年轻人和老年大鼠的记忆能力相关，但在海马记忆缺陷的老年大鼠中不存在这种关联。与当前临床前转化研究强调促进允许基因表达的染色质修饰相比，我们的研究结果表明，海马衰老的最佳成功可能取决于能否实现表观遗传景观的协调控制。
Mounting evidence linking epigenetic regulation to memory-related synaptic plasticity raises the possibility that altered chromatin modification dynamics might contribute to age-dependent cognitive decline. Here we show that the coordinated orchestration of both baseline and experience-dependent epigenetic regulation seen in the young adult hippocampus is lost in association with cognitive aging. Using a well-characterized rat model that reliably distinguishes aged individuals with significant memory impairment from others with normal memory, no single epigenetic mark or experience-dependent modification in the hippocampus uniquely predicted differences in the cognitive outcome of aging. The results instead point to a multivariate pattern in which modification-specific, bidirectional chromatin regulation is dependent on recent behavioral experience, chronological age, cognitive status, and hippocampal region. Whereas many epigenetic signatures were coupled with memory capacity among young adults and aged rats with preserved cognitive function, such associations were absent among aged rats with deficits in hippocampal memory. By comparison with the emphasis in current preclinical translational research on promoting chromatin modifications permissive for gene expression, our findings suggest that optimally successful hippocampal aging may hinge instead on enabling coordinated control across the epigenetic landscape.
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影响因子：
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作者：
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通讯作者：
Mann, Matthias
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