Comparative analysis reveals distinctive epigenetic features of the human cerebellum.
Comparative analysis reveals distinctive epigenetic features of the human cerebellum.
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DOI：
10.1371/journal.pgen.1009506
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发表时间：
2021-05
期刊：
影响因子：
4.5
通讯作者：
Sherwood CC
中科院分区：
文献类型：
--
作者：
Guevara EE;Hopkins WD;Hof PR;Ely JJ;Bradley BJ;Sherwood CC
确定人类认知和行为特征的神经特化的分子基础一直是相当大的兴趣。许多关于基因表达和表观遗传标记的人类特异性变化的研究都集中在前额叶皮层上，这是一种以其在执行功能中的作用而闻名的大脑结构。小脑在类人猿中表现出扩张，并因其在运动技能和认知过程（包括语言）中的作用而越来越受到关注。然而，相对较少的分子研究小脑在比较进化的背景下进行。在这里，我们确定了人类特异性甲基化的侧小脑相对于背外侧前额叶皮层，在与黑猩猩（Pan troglodytes）和恒河猴（Macaca mulatta）的比较研究。具体来说，我们分析了三个物种中两种大脑结构的全基因组甲基化水平，并确定了每个结构所特有的人类特异性差异甲基化基因组区域。我们进一步确定了哪些差异甲基化区域（DMR）与可能的调控元件重叠，并确定相关基因是否在基因表达中显示相应的物种差异。我们发现小脑中的人类特异性甲基化比背外侧前额叶皮层更大，差异甲基化区域与涉及与人类神经生物学相关的几种条件或过程的基因重叠，包括突触可塑性，脂质代谢，神经炎症和神经变性，以及神经发育，包括发育障碍。此外，我们的研究结果与以前专注于新皮层的研究结果有一些重叠，表明这些结果可能是多种大脑结构所共有的。这些发现进一步加深了我们对人类大脑进化中小脑的理解。人类与其他物种的区别在于认知的几个方面。虽然许多比较进化神经科学都集中在新皮层上，但越来越多的人认识到小脑在认知和运动处理中的作用，这激发了相当多的新研究。然而，比较分子学研究通常继续关注新皮层。我们试图通过对外侧小脑进行全基因组表观遗传分析来表征区分人类小脑的潜在遗传调控特征，并将其与人类，黑猩猩和恒河猴的前额叶皮层进行比较。我们发现，人类表现出更大的差异CpG甲基化-DNA的表观遗传修饰，可以反映过去或现在的基因表达-在小脑比前额皮质，突出了这个结构在人类大脑进化的重要性。人类还特别显示出参与神经发育、神经炎症、突触可塑性和脂质代谢的基因的甲基化差异。这些差异与理解人类特有的过程有关，例如广泛的可塑性，以及与衰老相关的明显和普遍的神经退行性疾病。
Identifying the molecular underpinnings of the neural specializations that underlie human cognitive and behavioral traits has long been of considerable interest. Much research on human-specific changes in gene expression and epigenetic marks has focused on the prefrontal cortex, a brain structure distinguished by its role in executive functions. The cerebellum shows expansion in great apes and is gaining increasing attention for its role in motor skills and cognitive processing, including language. However, relatively few molecular studies of the cerebellum in a comparative evolutionary context have been conducted. Here, we identify human-specific methylation in the lateral cerebellum relative to the dorsolateral prefrontal cortex, in a comparative study with chimpanzees (Pan troglodytes) and rhesus macaques (Macaca mulatta). Specifically, we profiled genome-wide methylation levels in the three species for each of the two brain structures and identified human-specific differentially methylated genomic regions unique to each structure. We further identified which differentially methylated regions (DMRs) overlap likely regulatory elements and determined whether associated genes show corresponding species differences in gene expression. We found greater human-specific methylation in the cerebellum than the dorsolateral prefrontal cortex, with differentially methylated regions overlapping genes involved in several conditions or processes relevant to human neurobiology, including synaptic plasticity, lipid metabolism, neuroinflammation and neurodegeneration, and neurodevelopment, including developmental disorders. Moreover, our results show some overlap with those of previous studies focused on the neocortex, indicating that such results may be common to multiple brain structures. These findings further our understanding of the cerebellum in human brain evolution. Humans are distinguished from other species by several aspects of cognition. While much comparative evolutionary neuroscience has focused on the neocortex, increasing recognition of the cerebellum’s role in cognition and motor processing has inspired considerable new research. Comparative molecular studies, however, generally continue to focus on the neocortex. We sought to characterize potential genetic regulatory traits distinguishing the human cerebellum by undertaking genome-wide epigenetic profiling of the lateral cerebellum, and compared this to the prefrontal cortex of humans, chimpanzees, and rhesus macaque monkeys. We found that humans showed greater differential CpG methylation–an epigenetic modification of DNA that can reflect past or present gene expression–in the cerebellum than the prefrontal cortex, highlighting the importance of this structure in human brain evolution. Humans also specifically show methylation differences at genes involved in neurodevelopment, neuroinflammation, synaptic plasticity, and lipid metabolism. These differences are relevant for understanding processes specific to humans, such as extensive plasticity, as well as pronounced and prevalent neurodegenerative conditions associated with aging.
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