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Human Organoids Aid Identification of Key Regulator in Cell Differentiation

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The different cell types of the human gut develop from stem cells through a process of differentiation. Researchers from the Organoid group (Hubrecht Institute), together with researchers at the Princess Máxima Center and Maastricht University, used gut organoids to perform a systematic CRISPR screening of 1800 human transcription factors and identified ZNF800 as a key regulator of the differentiation of a specific gut cell type, the enteroendocrine cells. The results of the study were published in Science on 26 October 2023 and could have implications for our understanding of gastrointestinal diseases and endocrine disorders, as well as pancreatic development and diabetes.

The human gut contains various cell types, each with specific functions. These cell types all arise from the stem cells of the gut: cells that are not specialized yet, but have the potential to become functionally specialized cells. Important cell types of the gut are enterocytes, responsible for the absorption of nutrients, goblet cells, which produce mucus, Paneth cells, which secrete antimicrobial peptides, and enteroendocrine cells (EECs), which produce various hormones. The hormones produced by the EECs regulate digestive processes, such as nutrient absorption, appetite and glucose metabolism. In this study, researchers from the Organoid group investigated how stem cells become EECs through a process called differentiation. For this they used gut organoids: lab-grown miniature organs that mimic the structure and function of the actual gut.

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Stem cell traffic lights

The differentiation of stem cells into specific cell types occurs through gene regulation: the ‘on’ and ‘off’ switching of genes in the DNA of the cells. Proteins called transcription factors play an important role in gene regulation, as it is their job to perform the on-off switching of genes. First author Lin Lin explains: “You can compare it to a bustling intersection where different roads lead to various cell destinies, and the vehicles on the roads symbolize different cell types. The transcription factors act as traffic lights at the intersections, determining whether cells can follow a particular direction to become specialized cells. In our study, we used CRISPR technology, a gene-editing tool, to specifically target individual transcription factors. This is like switching the ‘traffic lights’ on or off. By doing this, we aimed to uncover the intricate signaling system that directs cells down their predetermined routes, in the same way that traffic lights govern the movement of vehicles in a busy city.”

Clinical implications

The discoveries made by Lin and her colleagues could have implications for understanding gastrointestinal diseases and endocrine disorders. “Our findings provide crucial insights into the molecular mechanisms that govern cell fate decisions in the human gut, which is essential for understanding these conditions and ultimately developing treatments,” says Lin. The fact that ZNF800 was shown to affect other transcription factors such as PAX4 and NEUROG3 suggests there could also be implications for diabetes research. “These transcription factors are crucial for the regulation of insulin-producing beta cells in the pancreas, raising the possibility that ZNF800 may also play a role in pancreatic development and diabetes,” concludes Lin.

Reference: Lin L, DeMartino J, Wang D, et al. Unbiased transcription factor CRISPR screen identifies ZNF800 as master repressor of enteroendocrine differentiation. Science. 2023;382(6669):451-458. doi: 10.1126/science.adi2246

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.