UTX and 53BP1 co-regulate genetic programs for neural differentiation of human embryonic stem cells [RNA-seq]

UTX is a histone H3 lysine 27 demethylase required for development. However, the mechanisms underlying developmental gene regulation by UTX are unclear. Here, we discovered a molecular interaction between UTX and 53BP1 that regulates gene expression in a human neurogenesis model. Human 53BP1 contains a UTX-binding site that diverges from its mouse homolog by 41%, and our data suggest that the UTX-53BP1 interaction is conserved in primates but not rodents. ChIP-Seq revealed that the genome-wide targets of UTX and 53BP1 overlap by 84%. We used CRISPR-Cas9 to generate mutations of 53BP1 and UTX in human embryonic stem cells, and found that both 53BP1 and UTX are required to promote the expression of hundreds of neurogenic genes during neural differentiation. Further, 53BP1 is required for human neural progenitor differentiation into neurons. Our findings suggest that the UTX-53BP1 interaction controls gene expression important for neural differentiation in humans.

UTX（组蛋白H3赖氨酸27去甲基化酶，histone H3 lysine 27 demethylase）是发育过程所必需的组蛋白去甲基化酶。然而，UTX调控发育相关基因表达的具体分子机制尚未阐明。本研究中，我们在人类神经发生模型中发现，UTX与53BP1之间的分子相互作用可调控基因表达。人类53BP1存在一个与其小鼠同源序列存在41%序列差异的UTX结合位点，我们的数据表明，UTX与53BP1的相互作用在灵长类动物中具有保守性，但在啮齿类动物中并不保守。染色质免疫沉淀测序（Chromatin Immunoprecipitation Sequencing，ChIP-Seq）分析显示，UTX与53BP1的全基因组靶基因重叠率高达84%。我们借助CRISPR-Cas9技术在人类胚胎干细胞中构建了53BP1与UTX的基因突变体，发现在神经分化过程中，53BP1与UTX均是促进数百种神经发生相关基因表达所必需的。进一步研究表明，53BP1对于人类神经前体细胞向神经元的分化同样不可或缺。本研究结果表明，UTX与53BP1的相互作用可调控对人类神经分化至关重要的基因表达。