Transcription factor dynamics, oscillation, and functions in human enteroendocrine cell differentiation

IF 19.8 1区 医学 Q1 CELL & TISSUE ENGINEERING Cell stem cell Pub Date : 2024-05-10 DOI:10.1016/j.stem.2024.04.015
Pratik N.P. Singh, Wei Gu, Shariq Madha, Allen W. Lynch, Paloma Cejas, Ruiyang He, Swarnabh Bhattacharya, Miguel Muñoz Gomez, Matthew G. Oser, Myles Brown, Henry W. Long, Clifford A. Meyer, Qiao Zhou, Ramesh A. Shivdasani
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Abstract

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 cis-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 ASCL1+ and HES6hi 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 cis-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.

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人类肠内分泌细胞分化过程中转录因子的动态、振荡和功能
肠内分泌细胞(EECs)分泌血清素(肠粘膜细胞[EC])或特定的肽类激素(非肠粘膜细胞),发挥着重要的新陈代谢功能。终端 EEC 多样性的基础仍然模糊不清。通过强迫转录因子(TF)NEUROG3在人类肠干细胞二维培养物中的活性,我们复制了EEC的生理性分化,并研究了最终形成不同细胞类型的转录和顺式调控动态。丰富的EEC前体表达了阶段特异性基因和TFs。在表达前端 NEUROD1 之前,有丝分裂后的前体在转录不同的 ASCL1+ 和 HES6hi 细胞状态之间摇摆。ASCL1或NEUROD1的缺失对EC和非EC细胞特征的影响截然相反。这些TF主要与未分化干细胞中可接触到的顺式元件结合,它们可调整TF组合的后续表达,而这些TF组合是EEC离散特性的基础。因此,早期TF振荡会延缓EEC的成熟,从而使这一医学上重要的细胞系具有准确的多样性。
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来源期刊
Cell stem cell
Cell stem cell 生物-细胞生物学
CiteScore
37.10
自引率
2.50%
发文量
151
审稿时长
42 days
期刊介绍: Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.
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