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 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

doi:10.1126/science.adi2246

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 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

196 Downloads (Pure)

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.

Original language	English
Pages (from-to)	451-458
Number of pages	8
Journal	Science
Volume	382
Issue number	6669
DOIs	https://doi.org/10.1126/science.adi2246
Publication status	Published - 27 Oct 2023

Access to Document

10.1126/science.adi2246

Full TextFinal published version, 2.56 MBLicence: Taverne

Cite this

Lin, L., DeMartino, J., Wang, D., van Son, G. J. F., van der Linden, R., Begthel, H., Korving, J., Andersson-Rolf, A., van den Brink, S., Lopez-Iglesias, C., van de Wetering, W. J., Balwierz, A., Margaritis, T., van de Wetering, M., Peters, P. J., Drost, J., van Es, J. H., & Clevers, H. (2023). Unbiased transcription factor CRISPR screen identifies ZNF800 as master repressor of enteroendocrine differentiation. Science, 382(6669), 451-458. https://doi.org/10.1126/science.adi2246

@article{b5bd429abc2c456580caa6274a042917,

title = "Unbiased transcription factor CRISPR screen identifies ZNF800 as master repressor of enteroendocrine differentiation",

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.",

author = "Lin Lin and Jeff DeMartino and Daisong Wang and \{van Son\}, \{Gijs J.F.\} and \{van der Linden\}, Reinier and Harry Begthel and Jeroen Korving and Amanda Andersson-Rolf and \{van den Brink\}, Stieneke and Carmen Lopez-Iglesias and \{van de Wetering\}, \{Willine J.\} and Aleksandra Balwierz and Thanasis Margaritis and \{van de Wetering\}, Marc and Peters, \{Peter J.\} and Jarno Drost and \{van Es\}, \{Johan H.\} and Hans Clevers",

year = "2023",

month = oct,

day = "27",

doi = "10.1126/science.adi2246",

language = "English",

volume = "382",

pages = "451--458",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6669",

}

Lin, L, DeMartino, J, Wang, D, van Son, GJF, van der Linden, R, Begthel, H, Korving, J, Andersson-Rolf, A, van den Brink, S, Lopez-Iglesias, C, van de Wetering, WJ, Balwierz, A, Margaritis, T, van de Wetering, M, Peters, PJ, Drost, J, van Es, JH & Clevers, H 2023, 'Unbiased transcription factor CRISPR screen identifies ZNF800 as master repressor of enteroendocrine differentiation', Science, vol. 382, no. 6669, pp. 451-458. https://doi.org/10.1126/science.adi2246

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.

U2 - 10.1126/science.adi2246

DO - 10.1126/science.adi2246

M3 - Article

SN - 0036-8075

VL - 382

SP - 451

EP - 458

JO - Science

JF - Science

IS - 6669

ER -

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

Abstract

Access to Document

Fingerprint

Cite this