Epigenetic mechanism underlying human brain development identified

Promulgator:SLSTRelease time:2021-01-17 Views:10

On January 15, 2021, Professor Luo Zhenge and his colleagues at the School of Life Science and Technology (SLST) published a paper entitled, “TBC1D3 promotes neural progenitor proliferation by suppressing the histone methyltransferase G9a”, in the journal Science Advances

The cerebral cortex of mammals controls sensory input, motor output, learning and memory, decision-making and cognition. The expansion of the cerebral cortex during primate evolution is assumed to be associated with the acquisition of higher intelligence especially in humans. This process involves increased proliferative ability of cortical neural progenitors (NPs), which give rise to neurons or glia cells. It has been shown that epigenetic mechanisms, especially modifications of chromatin, play a critical role in regulating transcriptional programs governing the stemness of NPs. However, the role of epigenetic factors in the process of cortical expansion during human evolution remains to be explored.

Previously, Professor Luo Zhenge’s group found that the hominoid-specific gene TBC1D3 displays robust capacity for promoting the generation and proliferation of NPs, and contributes to cortical expansion. However, the underlying mechanisms have remained unclear. This paper describes their finding 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 displays an inhibitory role in G9a’s histone methyltransferase activity. Treatment with G9a inhibitor markedly increases NP proliferation and promotes human cerebral organoid expansion, mimicking the effects caused by TBC1D3 up-regulation. By contrast, blockade of TBC1D3/G9a interaction to disinhibit G9a causes up-regulation of H3K9me2, suppressing NP proliferation and impairing organoid development. Together, these findings have demonstrated a mechanism underlying the role of a hominoid-specific gene in promoting cortical expansion. 

The first author of this paper is Hou Qiongqiong, a postdoctoral fellow supervised by Professor Luo Zhenge. This study was partially supported by grants from National Natural Science Foundation of China, the Frontier Key Project of the Chinese Academy of Sciences, Shanghai Municipal Science and Technology Major Project, and a start-up support by ShanghaiTech University.



A proposed model showing a role of TBC1D3 in promoting NP proliferation and cortex expansion through down-regulating the level of H3K9me2

Link of the article: https://advances.sciencemag.org/content/7/3/eaba8053