PAUPAR/PAX6/NSD1 Complex Specificity Regulates Human Embryonic Stem Cell Dorsal Telencephalon Differentiation

Long noncoding RNAs (lncRNAs) play a wide range roles in the epigenetic regulation of crucial biological processes, but the functions of lncRNAs in cortical development are poorly understood. Using human embryonic stem cell (hESC)-based models of neural differentiation and organoid differentiation, we identified that the lncRNA PAUPAR, which is adjacent to PAX6, plays essential roles in dorsal telencephalon differentiation by interacting with PAX6 to regulate the expression of a large number of neural genes. Mechanistic studies showed that PAUPAR confers PAX6 proper binding site on the target neural genes by directly binding the genomic regions of these genes. Moreover, PAX6 recruits the histone methyltransferase NSD1 through its C-terminal PST enrichment domain, then regulate H3K36 methylation and the expression of target genes. Collectively, our data reveal that the PAUPAR/PAX6/NSD1 complex plays a critical role in the epigenetic regulation of hESC dosal telencephalon differentiation and highlight the importance of PAUPAR as an intrinsic regulator of cortical differentiation.