Genomic changes during human linage evolution contribute to the expansion of the cerebral cortex to allow more advanced thought processes. The hominoid-specific gene TBC1D3 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 N-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，从而允许更高级的思维过程。类人猿特异性基因TBC1D3显示出促进神经祖细胞 (NPs) 产生和增殖的强大能力，这被认为有助于皮层扩张。然而，潜在的机制仍不清楚。在这里，我们发现 TBC1D3 与 G9a 相互作用，常染色组蛋白赖氨酸N-甲基转移酶，介导赖氨酸 9 (H3K9me2) 中组蛋白 3 的二甲基化，这是基因表达的抑制标记。TBC1D3 在 G9a 的组蛋白甲基转移酶活性中显示出抑制作用。用 G9a 抑制剂治疗显着增加 NP 增殖并促进人脑类器官扩张，模仿 TBC1D3 上调引起的影响。相比之下，阻断 TBC1D3/G9a 相互作用以抑制 G9a 会导致 H3K9me2 上调，抑制 NP 增殖，并损害类器官发育。总之，这项研究证明了类人猿特异性基因在促进皮层扩张中的作用的潜在机制。