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