Enteroendocrine cells (EECs) secrete serotonin (enterochromaffin [EC] cells) or specific peptide hormones (non-EC cells) that serve vital metabolic functions. The basis for terminal EEC diversity remains obscure. By forcing activity of the transcription factor (TF) NEUROG3 in 2D cultures of human intestinal stem cells, we replicated physiologic EEC differentiation and examined transcriptional and -regulatory dynamics that culminate in discrete cell types. Abundant EEC precursors expressed stage-specific genes and TFs. Before expressing pre-terminal NEUROD1, post-mitotic precursors oscillated between transcriptionally distinct and cell states. Loss of either factor accelerated EEC differentiation substantially and disrupted EEC individuality; ASCL1 or NEUROD1 deficiency had opposing consequences on EC and non-EC cell features. These TFs mainly bind -elements that are accessible in undifferentiated stem cells, and they tailor subsequent expression of TF combinations that underlie discrete EEC identities. Thus, early TF oscillations retard EEC maturation to enable accurate diversity within a medically important cell lineage.

中文翻译：

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人肠内分泌细胞分化中的转录因子动力学、振荡和功能


肠内分泌细胞 (EEC) 分泌血清素（肠嗜铬 [EC] 细胞）或特定的肽激素（非 EC 细胞），发挥重要的代谢功能。终端 EEC 多样性的基础仍然模糊。通过在人类肠道干细胞的二维培养物中强制转录因子 (TF) NEUROG3 的活性，我们复制了 EEC 的生理分化，并检查了最终形成离散细胞类型的转录和调节动态。丰富的 EEC 前体表达阶段特异性基因和 TF。在表达前末端 NEUROD1 之前，有丝分裂后前体在转录不同状态和细胞状态之间振荡。任何一个因素的丧失都会大大加速 EEC 的分化并破坏 EEC 的个性； ASCL1 或 NEUROD1 缺陷对 EC 和非 EC 细胞特征产生相反的影响。这些转录因子主要结合未分化干细胞中可接近的元素，并且它们定制了构成离散 EEC 特性的转录因子组合的后续表达。因此，早期的 TF 振荡会延迟 EEC 的成熟，从而在医学上重要的细胞谱系中实现准确的多样性。