Department of Organismic and Evolutionary Biology, Museum of Comparative Zoology, Harvard University, Cambridge, MA 02138.
Department of Molecular and Cell Biology, Harvard University, Cambridge, MA 02138.
Proc Natl Acad Sci U S A. 2024 Jul 16;121(29):e2322864121. doi: 10.1073/pnas.2322864121. Epub 2024 Jul 8.
Animals capable of whole-body regeneration can replace any missing cell type and regenerate fully functional new organs, including new brains, de novo. The regeneration of a new brain requires the formation of diverse neural cell types and their assembly into an organized structure with correctly wired circuits. Recent work in various regenerative animals has revealed transcriptional programs required for the differentiation of distinct neural subpopulations, however, how these transcriptional programs are initiated in response to injury remains unknown. Here, we focused on the highly regenerative acoel worm, , to study wound-induced transcriptional regulatory events that lead to the production of neurons and subsequently a functional brain. Footprinting analysis using chromatin accessibility data on a chromosome-scale genome assembly revealed that binding sites for the Nuclear Factor Y (NFY) transcription factor complex were significantly bound during regeneration, showing a dynamic increase in binding within one hour upon amputation specifically in tail fragments, which will regenerate a new brain. Strikingly, NFY targets were highly enriched for genes with neuronal function. Single-cell transcriptome analysis combined with functional studies identified stem cells as a putative progenitor population for multiple neural subtypes. Further, we found that wound-induced expression is likely under direct transcriptional control by NFY, uncovering a mechanism for the initiation of a neural differentiation pathway by early wound-induced binding of a transcriptional regulator.
能够进行全身再生的动物能够替代任何缺失的细胞类型，并重新生成全新的、具有完整功能的器官，包括全新的大脑。新大脑的再生需要形成多样化的神经细胞类型，并将它们组装成具有正确布线电路的有组织结构。在各种再生动物中的最新研究揭示了分化为不同神经亚群所需的转录程序，然而，这些转录程序如何响应损伤而启动仍然未知。在这里，我们专注于高度再生的腔肠动物， ，研究导致神经元产生并随后产生功能大脑的创伤诱导转录调控事件。使用染色体规模基因组组装的染色质可及性数据进行足迹分析表明，核因子 Y (NFY) 转录因子复合物的结合位点在再生过程中特异性地结合，在截肢后一小时内结合动态增加，特别是在将再生新大脑的尾部片段中。引人注目的是，NFY 靶标高度富集具有神经元功能的基因。单细胞转录组分析结合功能研究鉴定出 干细胞是多种神经亚型的潜在祖细胞群体。此外，我们发现，由 NFY 直接转录调控的 表达可能受到创伤诱导的直接转录调控，揭示了一种通过早期创伤诱导的转录调节剂结合来启动神经分化途径的机制。
