Aging is accompanied by aberrant gene expression that ultimately affects brain plasticity and the capacity to form long-term memories. Immediate-early genes (IEGs) play an active role in these processes. Using a rat model of normal cognitive aging, we found that the expression of Egr1 and c-Fos was associated with chronological age, whereas Arc was more tightly linked to cognitive outcomes in aging. More specifically, constitutive Arc expression was significantly elevated in aged rats with memory impairment compared to cognitively intact aged rats and young adult animals. Since alterations in the neuroepigenetic mechanisms that gate hippocampal gene expression are also associated with cognitive outcome in aging, we narrowed our focus on examining potential epigenetic mechanisms that may lead to aberrant Arc expression. Employing a multilevel analytical approach using bisulfite sequencing, chromatin immunoprecipitations, and micrococcal nuclease digestion, we identified CpG sites in the Arc promoter that were coupled to poor cognitive outcomes in aging, histone marks that were similarly coupled to spatial memory deficits, and nucleosome positioning that also varied depending on cognitive status. Together, these findings paint a diverse and complex picture of the Arc epigenetic landscape in cognitive aging and bolster a body of work, indicating that dysfunctional epigenetic regulation is associated with memory impairment in the aged brain.

中文翻译：

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正常认知衰老中弧表观遗传景观的调查。

衰老伴随着异常的基因表达，最终会影响大脑的可塑性和形成长期记忆的能力。即刻早期基因 (IEG) 在这些过程中发挥积极作用。使用正常认知衰老的大鼠模型，我们发现 Egr1 和 c-Fos 的表达与实际年龄相关，而 Arc 与衰老的认知结果更紧密相关。更具体地说，与认知完整的老年大鼠和年轻成年动物相比，具有记忆障碍的老年大鼠的组成型 Arc 表达显着升高。由于控制海马基因表达的神经表观遗传机制的改变也与衰老的认知结果相关，因此我们将重点缩小到检查可能导致异常 Arc 表达的潜在表观遗传机制上。通过使用亚硫酸氢盐测序、染色质免疫沉淀和微球菌核酸酶消化的多级分析方法，我们确定了 Arc 启动子中与衰老认知结果不良相关的 CpG 位点、与空间记忆缺陷类似的组蛋白标记以及核小体定位也因认知状态而异。总之，这些发现描绘了认知衰老中 Arc 表观遗传景观的多样化和复杂图景，并支持了一系列工作，表明功能失调的表观遗传调节与老年大脑的记忆障碍有关。与空间记忆缺陷类似的组蛋白标记，以及也因认知状态而异的核小体定位。总之，这些发现描绘了认知衰老中 Arc 表观遗传景观的多样化和复杂图景，并支持了一系列工作，表明功能失调的表观遗传调节与老年大脑的记忆障碍有关。与空间记忆缺陷类似的组蛋白标记，以及也因认知状态而异的核小体定位。总之，这些发现描绘了认知衰老中 Arc 表观遗传景观的多样化和复杂图景，并支持了一系列工作，表明功能失调的表观遗传调节与老年大脑的记忆障碍有关。