During differentiation, cells become structurally and functionally specialized, but comprehensive views of the underlying remodeling processes are elusive. Here, we leverage single-cell RNA sequencing (scRNA-seq) developmental trajectories to reconstruct differentiation using two secretory tissues as models—the zebrafish notochord and hatching gland. First, we integrated expression and functional similarities to identify gene modules, revealing dozens of modules representing known and newly associated differentiation processes and their dynamics. Second, we focused on the unfolded protein response (UPR) transducer module to study how general versus cell-type-specific secretory functions are regulated. Profiling loss- and gain-of-function embryos identified that the UPR transcription factors creb3l1, creb3l2, and xbp1 are master regulators of a general secretion program. creb3l1/creb3l2 additionally activate an extracellular matrix secretion program, while xbp1 partners with bhlha15 to activate a gland-like secretion program. Our study presents module identification via multi-source integration for reconstructing differentiation (MIMIR) and illustrates how transcription factors confer general and specialized cellular functions.

中文翻译：

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基因模块重建识别斑马鱼细胞分化过程和特化分泌的调控逻辑


在分化过程中，细胞在结构和功能上变得特化，但难以全面了解潜在的重塑过程。在这里，我们利用单细胞 RNA 测序 （scRNA-seq） 发育轨迹，使用两个分泌组织作为模型——斑马鱼脊索和孵化腺来重建分化。首先，我们整合了表达和功能相似性以识别基因模块，揭示了代表已知和新关联的分化过程及其动力学的数十个模块。其次，我们专注于未折叠蛋白反应 （UPR） 传感器模块，以研究一般与细胞类型特异性分泌功能如何调节。分析功能丧失和功能获得性胚胎确定 UPR 转录因子 creb3l1 、 creb3l2 和 xbp1 是一般分泌程序的主调节因子。CREB3L1/CREB3L2 还激活细胞外基质分泌程序，而 XBP1 与 BHRHA15 合作激活腺体样分泌程序。我们的研究通过多源整合重建分化 （MIMIR） 进行了模块识别，并说明了转录因子如何赋予一般和特殊的细胞功能。