Repression by PRDM13 is critical for generating precise neuronal identity (RNA-Seq)

The mechanisms that activate some genes while silencing others are critical to ensure precision in lineage specification as multipotent progenitors become restricted in cell fate. During neurodevelopment, these mechanisms are required to generate the wide variety of neuronal subtypes found in the nervous system. Here we report interactions between basic helix-loop-helix (bHLH) transcriptional activators and the transcriptional repressor PRDM13 that are critical for these processes during specification of dorsal spinal cord neurons. PRDM13 inhibits gene expression programs for the excitatory neuronal lineages in the dorsal neural tube while also suppressing a battery of genes that determine ventral neural tube fates including Olig1, Olig2 and Prdm12. PRDM13 does this via recruitment to chromatin by multiple neural bHLH factors to restrict gene expression in specific neuronal lineages. Together these findings highlight the function of PRDM13 in repressing bHLH transcriptional activators that together are required to achieve precise neuronal specification during development. RNA-seq analysis performed on GFP+ cells sorted by FACS from Prdm13GFP/+ or Prdm13GFP/GFP mouse E11.5 neural tubes to identify gene expression in the presence and absence of PRDM13.在多能祖细胞的分化潜能逐渐受限并走向特定细胞命运的过程中，选择性激活部分基因并沉默另一些基因的调控机制，对于确保细胞谱系特化的精准性至关重要。在神经发育阶段，此类调控机制是产生神经系统中各类神经元亚型的必要前提。本研究报道了碱性螺旋-环-螺旋（basic helix-loop-helix, bHLH）转录激活因子与转录抑制因子PRDM13之间的相互作用，该相互作用对于背侧脊髓神经元特化过程中的上述调控环节至关重要。PRDM13可抑制背侧神经管内兴奋性神经元谱系的基因表达程序，同时还能沉默一系列决定腹侧神经管命运的基因，其中包括Olig1、Olig2及Prdm12。PRDM13通过被多种神经bHLH因子招募至染色质，从而在特定神经元谱系中精准限制基因表达。综上，本研究结果揭示了PRDM13通过抑制bHLH转录激活因子发挥功能的核心机制，而此类激活因子共同参与并保障了发育过程中神经元特化的精准性。本研究针对从Prdm13GFP/+或Prdm13GFP/GFP小鼠胚胎E11.5神经管中通过荧光激活细胞分选（Fluorescence-Activated Cell Sorting, FACS）获取的GFP阳性细胞开展RNA测序（RNA-seq）分析，以此鉴定PRDM13存在与缺失状态下的基因表达特征。