Human-specific hypomethylation of CENPJ, a key brain size regulator.
Human-specific hypomethylation of CENPJ, a key brain size regulator.
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DOI：
10.1093/molbev/mst231
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发表时间：
2014-03
影响因子：
10.7
通讯作者：
Lei Shi;Qiang Lin;B. Su
中科院分区：
文献类型：
--
作者：
Lei Shi;Qiang Lin;B. Su
大脑扩大和同时高度发达的认知技能通常被视为使人类区别于其他灵长类动物的独特特征。尽管有这种明显的差异，但这种人类特有特征的遗传机制还不清楚。特别是，表观遗传调控是否可能在人类大脑进化中发挥关键作用仍然难以捉摸。在这项研究中，我们使用亚硫酸氢盐测序来比较四个已知基因的甲基化模式，这些基因调节前额叶皮层中的大脑大小（ASPM，CDK 5 RAP 2，CENPJ和MCPH 1），这些基因跨越灵长类动物的主要谱系（即，人类、类人猿、小型类人猿和旧大陆猴）。结果显示，大脑中CENPJ的5' UTR中存在人类特异性低甲基化，其中人类的甲基化水平仅为非人类灵长类动物的三分之一。在肝脏、肾脏和心脏组织中也检测到了类似的甲基化模式，尽管物种间的差异远不如大脑中的差异明显。进一步的体外甲基化分析表明，CENPJ启动子的甲基化状态可以影响其表达。我们还检测到CENPJ表达在人类和非人类灵长类动物的成年个体的大脑和整个胎儿大脑发育的主要阶段有很大的差异。CENPJ在人类中枢神经系统中的低甲基化和相对较高的表达表明，人类特异性的-并且可能是可遗传的-表观遗传修饰可能发生在人类进化过程中，可能导致人类大脑发育期间的神经祖细胞库更大，这可能最终导致大脑急剧扩大和与人类相关的高度发达的认知能力。
Both the enlarged brain and concurrent highly developed cognitive skills are often seen as distinctive characteristics that set humans apart from other primates. Despite this obvious differentiation, the genetic mechanisms that underlie such human-specific traits are not clearly understood. In particular, whether epigenetic regulations may play a key role in human brain evolution remain elusive. In this study, we used bisulfite sequencing to compare the methylation patterns of four known genes that regulate brain size (ASPM, CDK5RAP2, CENPJ, and MCPH1) in the prefrontal cortex among several primate species spanning the major lineages of primates (i.e., humans, great apes, lesser apes, and Old World monkeys). The results showed a human-specific hypomethylation in the 5' UTR of CENPJ in the brain, where methylation levels among humans are only about one-third of those found among nonhuman primates. Similar methylation patterns were also detected in liver, kidney, and heart tissues, although the between-species differences were much less pronounced than those in the brain. Further in vitro methylation assays indicated that the methylation status of the CENPJ promoter could influence its expression. We also detected a large difference in CENPJ expression in the human and nonhuman primate brains of both adult individuals and throughout the major stages of fetal brain development. The hypomethylation and comparatively high expression of CENPJ in the central nervous system of humans suggest that a human-specific--and likely heritable--epigenetic modification likely occurred during human evolution, potentially leading to a much larger neural progenitor pool during human brain development, which may have eventually contributed to the dramatically enlarged brain and highly developed cognitive abilities associated with humans.