Sequence logic at enhancers governs a dual mechanism of endodermal organ fate induction by FOXA pioneer factors.

Binding Sites Cell Differentiation Embryonic Stem Cells / cytology Endoderm / embryology Enhancer Elements, Genetic / genetics Gene Expression Regulation, Developmental Hepatocyte Nuclear Factor 3-alpha / metabolism Hepatocyte Nuclear Factor 3-beta / metabolism Homeodomain Proteins / genetics Humans Liver / embryology Lung / embryology Nucleotide Motifs Organ Specificity Organogenesis Pancreas / embryology Trans-Activators / genetics

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
17 11 2021
Historique:
received: 29 10 2020
accepted: 28 10 2021
entrez: 18 11 2021
pubmed: 19 11 2021
medline: 16 12 2021
Statut: epublish

Résumé

FOXA pioneer transcription factors (TFs) associate with primed enhancers in endodermal organ precursors. Using a human stem cell model of pancreas differentiation, we here discover that only a subset of pancreatic enhancers is FOXA-primed, whereas the majority is unprimed and engages FOXA upon lineage induction. Primed enhancers are enriched for signal-dependent TF motifs and harbor abundant and strong FOXA motifs. Unprimed enhancers harbor fewer, more degenerate FOXA motifs, and FOXA recruitment to unprimed but not primed enhancers requires pancreatic TFs. Strengthening FOXA motifs at an unprimed enhancer near NKX6.1 renders FOXA recruitment pancreatic TF-independent, induces priming, and broadens the NKX6.1 expression domain. We make analogous observations about FOXA binding during hepatic and lung development. Our findings suggest a dual role for FOXA in endodermal organ development: first, FOXA facilitates signal-dependent lineage initiation via enhancer priming, and second, FOXA enforces organ cell type-specific gene expression via indirect recruitment by lineage-specific TFs.

Identifiants

DOI: 10.1038/s41467-021-26950-0 PMID: 34789735 PMC: PMC8599738
pubmed: 34789735
doi: 10.1038/s41467-021-26950-0
pii: 10.1038/s41467-021-26950-0
pmc: PMC8599738
doi:

Substances chimiques

FOXA1 protein, human 0
FOXA2 protein, human 0
Hepatocyte Nuclear Factor 3-alpha 0
Homeodomain Proteins 0
NKX6-1 protein, human 0
Trans-Activators 0
pancreatic and duodenal homeobox 1 protein 0
Hepatocyte Nuclear Factor 3-beta 135845-92-0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

6636

Subventions

Organisme : NIDDK NIH HHS
ID : P30 DK063491
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008666
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK068471
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK078803
Pays : United States
Organisme : NIDDK NIH HHS
ID : U54 DK107977
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL095993
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128172
Pays : United States
Organisme : NCATS NIH HHS
ID : U01 TR001810
Pays : United States

Informations de copyright

© 2021. The Author(s).

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Auteurs

Ryan J Geusz (RJ)

Department of Pediatrics, Pediatric Diabetes Research Center, University of California, La Jolla, San Diego, CA, 92093, USA.
Department of Cellular & Molecular Medicine, University of California, La Jolla, San Diego, CA, 92093, USA.
Sanford Consortium for Regenerative Medicine, La Jolla, San Diego, CA, 92093, USA.
Biomedical Graduate Studies Program, University of California San Diego, La Jolla, San Diego, CA, 92037, USA.
ORCID: 0000-0002-4897-9305

Allen Wang (A)

Department of Pediatrics, Pediatric Diabetes Research Center, University of California, La Jolla, San Diego, CA, 92093, USA.
Department of Cellular & Molecular Medicine, University of California, La Jolla, San Diego, CA, 92093, USA.
Sanford Consortium for Regenerative Medicine, La Jolla, San Diego, CA, 92093, USA.

Dieter K Lam (DK)

Department of Pediatrics, Pediatric Diabetes Research Center, University of California, La Jolla, San Diego, CA, 92093, USA.
Department of Cellular & Molecular Medicine, University of California, La Jolla, San Diego, CA, 92093, USA.
Sanford Consortium for Regenerative Medicine, La Jolla, San Diego, CA, 92093, USA.

Nicholas K Vinckier (NK)

Department of Pediatrics, Pediatric Diabetes Research Center, University of California, La Jolla, San Diego, CA, 92093, USA.
Department of Cellular & Molecular Medicine, University of California, La Jolla, San Diego, CA, 92093, USA.
Sanford Consortium for Regenerative Medicine, La Jolla, San Diego, CA, 92093, USA.

Konstantinos-Dionysios Alysandratos (KD)

Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, 02118, USA.
The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA.

David A Roberts (DA)

Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, 02118, USA.

Jinzhao Wang (J)

Department of Pediatrics, Pediatric Diabetes Research Center, University of California, La Jolla, San Diego, CA, 92093, USA.
Department of Cellular & Molecular Medicine, University of California, La Jolla, San Diego, CA, 92093, USA.
Sanford Consortium for Regenerative Medicine, La Jolla, San Diego, CA, 92093, USA.
ORCID: 0000-0003-1595-9460

Samy Kefalopoulou (S)

Department of Pediatrics, Pediatric Diabetes Research Center, University of California, La Jolla, San Diego, CA, 92093, USA.
Department of Cellular & Molecular Medicine, University of California, La Jolla, San Diego, CA, 92093, USA.
Sanford Consortium for Regenerative Medicine, La Jolla, San Diego, CA, 92093, USA.

Araceli Ramirez (A)

Department of Pediatrics, Pediatric Diabetes Research Center, University of California, La Jolla, San Diego, CA, 92093, USA.
Department of Cellular & Molecular Medicine, University of California, La Jolla, San Diego, CA, 92093, USA.
Sanford Consortium for Regenerative Medicine, La Jolla, San Diego, CA, 92093, USA.

Yunjiang Qiu (Y)

Department of Cellular & Molecular Medicine, University of California, La Jolla, San Diego, CA, 92093, USA.
ORCID: 0000-0002-0539-9714

Joshua Chiou (J)

Department of Pediatrics, Pediatric Diabetes Research Center, University of California, La Jolla, San Diego, CA, 92093, USA.
Biomedical Graduate Studies Program, University of California San Diego, La Jolla, San Diego, CA, 92037, USA.
ORCID: 0000-0002-4618-0647

Kyle J Gaulton (KJ)

Department of Pediatrics, Pediatric Diabetes Research Center, University of California, La Jolla, San Diego, CA, 92093, USA.
ORCID: 0000-0003-1318-7161

Bing Ren (B)

Department of Cellular & Molecular Medicine, University of California, La Jolla, San Diego, CA, 92093, USA.
Ludwig Institute for Cancer Research, La Jolla, San Diego, CA, 92093-0653, USA.
ORCID: 0000-0002-5435-1127

Darrell N Kotton (DN)

Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, 02118, USA.
The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA.
ORCID: 0000-0002-9604-8476

Maike Sander (M)

Department of Pediatrics, Pediatric Diabetes Research Center, University of California, La Jolla, San Diego, CA, 92093, USA. masander@ucsd.edu.
Department of Cellular & Molecular Medicine, University of California, La Jolla, San Diego, CA, 92093, USA. masander@ucsd.edu.
Sanford Consortium for Regenerative Medicine, La Jolla, San Diego, CA, 92093, USA. masander@ucsd.edu.
ORCID: 0000-0001-5308-7785

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Classifications MeSH

questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Sites de fixation › Sequence logic at enhancers governs a dual...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Différenciation cellulaire › Sequence logic at enhancers governs a dual...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches embryonnaires › Sequence logic at enhancers governs a dual...
questionsmedicales.fr › Structures de l'embryon › Feuillets embryonnaires › Endoderme › Sequence logic at enhancers governs a dual...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Éléments de régulation transcriptionnelle › Éléments activateurs (génétique) › Sequence logic at enhancers governs a dual...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes au cours du développement › Sequence logic at enhancers governs a dual...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif hélice ailée › Facteurs de transcription Forkhead › Facteur nucléaire hépatocytaire HNF-3 alpha › Sequence logic at enhancers governs a dual...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif hélice ailée › Facteurs de transcription Forkhead › Facteur nucléaire hépatocytaire HNF-3 bêta › Sequence logic at enhancers governs a dual...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de liaison à l'ADN › Protéines à homéodomaine › Sequence logic at enhancers governs a dual...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Sequence logic at enhancers governs a dual...
questionsmedicales.fr › Système digestif › Foie › Sequence logic at enhancers governs a dual...
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questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Conformation d'acide nucléique › Motifs nucléotidiques › Sequence logic at enhancers governs a dual...
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questionsmedicales.fr › Système digestif › Pancréas › Sequence logic at enhancers governs a dual...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines virales › Protéines virales régulatrices ou accessoires › Transactivateurs › Sequence logic at enhancers governs a dual...