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

Author:

Lin Lin123ORCID,DeMartino Jeff23ORCID,Wang Daisong12,van Son Gijs J. F.23ORCID,van der Linden Reinier12ORCID,Begthel Harry12ORCID,Korving Jeroen12,Andersson-Rolf Amanda12,van den Brink Stieneke12,Lopez-Iglesias Carmen4,van de Wetering Willine J.4ORCID,Balwierz Aleksandra3ORCID,Margaritis Thanasis3ORCID,van de Wetering Marc23ORCID,Peters Peter J.4ORCID,Drost Jarno23ORCID,van Es Johan H.12,Clevers Hans123ORCID

Affiliation:

1. Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, Netherlands.

2. Oncode Institute, Utrecht, Netherlands.

3. Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands.

4. The Maastricht Multimodal Molecular Imaging Institute, Maastricht University, Maastricht, Netherlands.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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