TBC1D3 promotes neural progenitor proliferation by suppressing the histone methyltransferase G9a

Abstract

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.

Generation of vascularized brain organoids to study neurovascular interactions

“…Having established the VOrs, we decided to generate vascularized BOrs by using co-culture strategy. For this purpose, we established the induction system of BOrs from human H9 ESCs according to the methods reported previously ( Lancaster and Knoblich, 2014 ; Mariani et al, 2012 ; Ou et al, 2020 ; Hou et al, 2021 ), with some modifications ( Figure 4—figure supplement 1A ). Cerebral organoids at different developmental stages were stained with neural progenitor markers PAX6 and phospho-vimentin (p-VIM), the proliferation marker KI67, intermediate progenitor marker TBR2, young neuron marker DCX (doublecortin), mature neuron marker TUJ1, and the cortical layer markers (TBR1, CTIP2, SATB2, REELIN), and the results indicated that the BOrs were well induced ( Figure 4—figure supplement 1B–E ).…”

The human FOXM1 homolog promotes basal progenitor cell proliferation and cortical folding in mouse

“…Overproliferation of basal radial glial cells (bRGCs) increases cortical surface area and folding in primates (Reillo et al , 2011; Nonaka‐Kinoshita et al , 2013). Recently, some studies have shown that human‐specific genes promote cortical progenitor proliferation and expansion through different mechanisms by inhibiting histone methylation activity or glutaminolysis regulation (Deyama & Duman, 2020; Hou et al , 2021). Increased proliferation capacity of cortical progenitors is critical for cortical expansion.…”

Unraveling Human Brain Development and Evolution Using Organoid Models

“…They have also been shown to recapitulate transcriptomics and the epigenetic landscape of early to mid-fetal development (Luo et al, 2016). Researchers found that inhibition of G9a-mediated H3K9me2 modification in human cerebral organoids resulted in increased NPC proliferation causing organoid expansion, and G9a is likely regulated by the hominoid-specific protein TBC1D3 (Hou et al, 2021). These findings suggest an epigenetic regulatory mechanism for neocortical expansion and possibly ensuing gyrification.…”