Hou Qiong-Qiong, Xiao Qi, Sun Xin-Yao, Ju Xiang-Chun, Luo Zhen-Ge
School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China.
Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, 200031 Shanghai, China.
Sci Adv. 2021 Jan 15;7(3). doi: 10.1126/sciadv.aba8053. Print 2021 Jan.
Genomic changes during human linage evolution contribute to the expansion of the cerebral cortex to allow more advanced thought processes. The hominoid-specific gene displays robust capacity of promoting the generation and proliferation of neural progenitors (NPs), which are thought to contribute to cortical expansion. However, the underlying mechanisms remain unclear. Here, we found that TBC1D3 interacts with G9a, a euchromatic histone lysine -methyltransferase, which mediates dimethylation of histone 3 in lysine 9 (H3K9me2), a suppressive mark for gene expression. TBC1D3 displayed an inhibitory role in G9a's histone methyltransferase activity. Treatment with G9a inhibitor markedly increased NP proliferation and promoted human cerebral organoid expansion, mimicking the effects caused by TBC1D3 up-regulation. By contrast, blockade of TBC1D3/G9a interaction to disinhibit G9a caused up-regulation of H3K9me2, suppressed NP proliferation, and impaired organoid development. Together, this study has demonstrated a mechanism underlying the role of a hominoid-specific gene in promoting cortical expansion.
人类谱系进化过程中的基因组变化有助于大脑皮层的扩展，以实现更高级的思维过程。类人猿特异性基因表现出强大的促进神经祖细胞（NP）生成和增殖的能力，而神经祖细胞被认为有助于皮层扩展。然而，其潜在机制仍不清楚。在这里，我们发现TBC1D3与G9a相互作用，G9a是一种常染色质组蛋白赖氨酸甲基转移酶，介导组蛋白3赖氨酸9位点的二甲基化（H3K9me2），这是一种基因表达的抑制标记。TBC1D3对G9a的组蛋白甲基转移酶活性具有抑制作用。用G9a抑制剂处理可显著增加NP增殖并促进人脑类器官的扩展，这与TBC1D3上调所产生的效果相似。相反，阻断TBC1D3/G9a相互作用以解除对G9a的抑制会导致H3K9me2上调，抑制NP增殖，并损害类器官发育。总之，这项研究揭示了类人猿特异性基因在促进皮层扩展中作用的潜在机制。
