Unbiased transcription factor CRISPR screen identifies ZNF800 as master repressor of enteroendocrine differentiation.
Lin LinJeff DeMartinoDaisong WangGijs J F van SonReinier van der LindenHarry BegthelJeroen KorvingAmanda Andersson-RolfStieneke van den BrinkCarmen Lopez-IglesiasWilline J van de WeteringAleksandra BalwierzThanasis MargaritisMarc van de WeteringPeter J PetersJarno DrostJohan H van EsHans CleversPublished in: Science (New York, N.Y.) (2023)
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.
Keyphrases
- genome wide
- transcription factor
- cell fate
- induced apoptosis
- crispr cas
- genome editing
- dna methylation
- high throughput
- cell cycle arrest
- type diabetes
- endoplasmic reticulum stress
- genome wide identification
- room temperature
- metabolic syndrome
- quality improvement
- single cell
- adipose tissue
- weight loss
- skeletal muscle
- pluripotent stem cells