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

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Item Type:Article
Title:Sequence logic at enhancers governs a dual mechanism of endodermal organ fate induction by FOXA pioneer factors
Creators Name:Geusz, R.J. and Wang, A. and Lam, D.K. and Vinckier, N.K. and Alysandratos, K.D. and Roberts, D.A. and Wang, J. and Kefalopoulou, S. and Ramirez, A. and Qiu, Y. and Chiou, J. and Gaulton, K.J. and Ren, B. and Kotton, D.N. and Sander, M.
Abstract: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.
Keywords:Binding Sites, Cell Differentiation, Developmental Gene Expression Regulation, Embryonic Stem Cells, Endoderm, Genetic Enhancer Elements, Hepatocyte Nuclear Factor 3-alpha, Hepatocyte Nuclear Factor 3-beta, Homeodomain Proteins, Liver, Lung, Nucleotide Motifs, Organ Specificity, Organogenesis, Pancreas, Trans-Activators
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:6636
Date:17 November 2021
Official Publication:https://doi.org/10.1038/s41467-021-26950-0
PubMed:View item in PubMed

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