TY - JOUR
T1 - Unbiased transcription factor CRISPR screen identifies ZNF800 as master repressor of enteroendocrine differentiation
AU - Lin, Lin
AU - DeMartino, Jeff
AU - Wang, Daisong
AU - van Son, Gijs J F
AU - van der Linden, Reinier
AU - Begthel, Harry
AU - Korving, Jeroen
AU - Andersson-Rolf, Amanda
AU - van den Brink, Stieneke
AU - Lopez-Iglesias, Carmen
AU - van de Wetering, Willine J
AU - Balwierz, Aleksandra
AU - Margaritis, Thanasis
AU - van de Wetering, Marc
AU - Peters, Peter J
AU - Drost, Jarno
AU - van Es, Johan H
AU - Clevers, Hans
PY - 2023/10/27
Y1 - 2023/10/27
N2 - 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.
AB - 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.
KW - Humans
KW - Cell Differentiation/genetics
KW - CRISPR-Cas Systems
KW - Enteroendocrine Cells/cytology
KW - Gene Expression Regulation
KW - Organoids
KW - Zinc Fingers
KW - Adult
KW - Cell Lineage/genetics
KW - Repressor Proteins/genetics
U2 - 10.1126/science.adi2246
DO - 10.1126/science.adi2246
M3 - Article
C2 - 37883554
SN - 0036-8075
VL - 382
SP - 451
EP - 458
JO - Science
JF - Science
IS - 6669
ER -