Ning Chao, Wu Xi, Zhao Xudong, Lu Zongyang, Yao Xuelong, Zhou Tao, Yi Lizhi, Sun Yaoyu, Wu Shuaishuai, Liu Zhenbo, Huang Xingxu, Gao Lei, Liu Jiang
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
Natl Sci Rev. 2024 Jun 18;11(8):nwae213. doi: 10.1093/nsr/nwae213. eCollection 2024 Aug.
The prefrontal cortex (PFC) is essential for higher-level cognitive functions. How epigenetic dynamics participates in PFC development and aging is largely unknown. Here, we profiled epigenomic landscapes of rhesus monkey PFCs from prenatal to aging stages. The dynamics of chromatin states, including higher-order chromatin structure, chromatin interaction and histone modifications are coordinated to regulate stage-specific gene transcription, participating in distinct processes of neurodevelopment. Dramatic changes of epigenetic signals occur around the birth stage. Notably, genes involved in neuronal cell differentiation and layer specification are -configured by bivalent promoters. We identified a -regulatory module and the transcription factors (TFs) associated with basal radial glia development, which was associated with large brain size in primates. These TFs include GLI3, CREB5 and SOX9. Interestingly, the genes associated with the basal radial glia (bRG)-associated -element module, such as SRY and SOX9, are enriched in sex differentiation. Schizophrenia-associated single nucleotide polymorphisms are more enriched in super enhancers (SEs) than typical enhancers, suggesting that SEs play an important role in neural network wiring. A -regulatory element of is identified, which is critical for neuronal cell proliferation and synaptic neuron differentiation. Notably, the loss of distal chromatin interaction and H3K27me3 signal are hallmarks of PFC aging, which are associated with abnormal expression of aging-related genes and transposon activation, respectively. Collectively, our findings shed light on epigenetic mechanisms underlying primate brain development and aging.
前额叶皮层（PFC）对于高级认知功能至关重要。表观遗传动力学如何参与PFC的发育和衰老在很大程度上尚不清楚。在此，我们描绘了恒河猴PFC从产前到衰老阶段的表观基因组景观。染色质状态的动力学，包括高阶染色质结构、染色质相互作用和组蛋白修饰，协同调节阶段特异性基因转录，参与神经发育的不同过程。表观遗传信号在出生阶段前后发生显著变化。值得注意的是，参与神经元细胞分化和层特异性的基因由双价启动子配置。我们鉴定了一个调控模块以及与基底放射状胶质细胞发育相关的转录因子（TFs），这与灵长类动物的大脑尺寸较大有关。这些TFs包括GLI3、CREB5和SOX9。有趣的是，与基底放射状胶质细胞（bRG）相关的元件模块相关的基因，如SRY和SOX9，在性别分化中富集。精神分裂症相关的单核苷酸多态性在超级增强子（SEs）中比典型增强子更富集，表明SEs在神经网络连接中起重要作用。鉴定了一个的调控元件，它对神经元细胞增殖和突触神经元分化至关重要。值得注意的是，远端染色质相互作用的丧失和H3K27me3信号是PFC衰老的标志，分别与衰老相关基因的异常表达和转座子激活有关。总的来说，我们的发现揭示了灵长类动物大脑发育和衰老的表观遗传机制。
