研究人员表示，肠内分泌细胞（EEC）是驻留在胃、小肠（SI）和结肠上皮细胞中的激素分泌细胞。肠内分泌细胞调节新陈代谢活动的各个方面，包括胰岛素水平、饱腹感、胃肠道分泌和蠕动。目前还不完全清楚不同EEC谱系的生成过程。
研究人员报告了对成人SI器官组织中的全部转录因子（TF）进行CRISPR敲除筛选的结果，以确定控制EEC分化的核心TF。研究人员发现ZNF800是内分泌谱系确立的核心抑制因子，它通过直接控制以PAX4为中心的内分泌TF网络，特异性地限制了肠组织细胞的分化。因此，类器官模型允许对细胞命运编程基因进行无偏依的功能性CRISPR筛选。
附：英文原文
Title: Unbiased transcription factor CRISPR screen identifies ZNF800 as master repressor of enteroendocrine differentiation
Author: Lin Lin, Jeff DeMartino, Daisong Wang, Gijs J. F. van Son, Reinier van der Linden, Harry Begthel, Jeroen Korving, Amanda Andersson-Rolf, Stieneke van den Brink, Carmen Lopez-Iglesias, Willine J. van de Wetering, Aleksandra Balwierz, Thanasis Margaritis, Marc van de Wetering, Peter J. Peters, Jarno Drost, Johan H. van Es, Hans Clevers
Issue&Volume: 2023-10-27
Abstract: 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.
DOI: adi2246
Source: https://www.science.org/doi/10.1126/science.adi2246