Unbiased transcription factor CRISPR screen identifies ZNF800 as master repressor of enteroendocrine differentiation

• 成果类型: Article
• 署名作者: Lin, Lin; DeMartino, Jeff; Wang, Daisong; van Son, Gijs J. F.; van der Linden, Reinier; Begthel, Harry; Korving, Jeroen; Andersson-Rolf, Amanda; van den Brink, Stieneke; Lopez-Iglesias, Carmen; van de Wetering, Willine J.; Balwierz, Aleksandra; Margaritis, Thanasis; van de Wetering, Marc; Peters, Peter J.; Drost, Jarno; van Es, Johan H.; Clevers, Hans
• 署名单位: Royal Netherlands Academy of Arts & Sciences; Hubrecht Institute (KNAW); Princess Maxima Center; Maastricht University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10645
• DOI: 10.1126/science.adi2246
• 发表日期: 2023-10-27
• 页码: 451-458
• 关键词: cell fate specification; stem-cells; small-intestine; expression; genes; organoids; lineages; pax4; arx; neurogenin3

摘要

Enteroendocrine cells (EECs) are hormone-producing cells residing in the epithelium of stomach, small intestine (SI), and colon. EECs regulate aspects of metabolic activity, including insulin levels, satiety, gastrointestinal secretion, and motility. The generation of different EEC lineages is not completely understood. In this work, we report a CRISPR knockout screen of the entire repertoire of transcription factors (TFs) in adult human SI organoids to identify dominant TFs controlling EEC differentiation. We discovered ZNF800 as a master repressor for endocrine lineage commitment, which particularly restricts enterochromaffin cell differentiation by directly controlling an endocrine TF network centered on PAX4. Thus, organoid models allow unbiased functional CRISPR screens for genes that program cell fate.