Sequence logic at enhancers governs a dual mechanism of endodermal organ fate induction by FOXA pioneer factors
| Autor: | Dieter K Lam, Konstantinos-Dionysios Alysandratos, Samy Kefalopoulou, Joshua Chiou, Darrell N. Kotton, Kyle J Gaulton, Nicholas K Vinckier, Allen Y. Wang, Bing Ren, Jinzhao Wang, Yunjiang Qiu, Araceli Ramirez, Maike Sander, David A. Roberts, Ryan J Geusz |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Hepatocyte Nuclear Factor 3-alpha
Embryonic stem cells Lineage (genetic) animal structures Enhancer Elements Organogenesis Science Cell General Physics and Astronomy Priming (immunology) Biology General Biochemistry Genetics and Molecular Biology Article Rare Diseases Genetic Gene expression medicine Humans Developmental Gastrointestinal models Nucleotide Motifs Enhancer Transcription factor Lung Pancreas Embryonic Stem Cells Homeodomain Proteins Multidisciplinary Binding Sites Endoderm fungi Gene Expression Regulation Developmental Cell Differentiation General Chemistry Stem Cell Research Cell biology medicine.anatomical_structure Enhancer Elements Genetic Gene Expression Regulation Liver Organ Specificity embryonic structures Hepatocyte Nuclear Factor 3-beta Trans-Activators Stem cell Digestive Diseases |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-19 (2021) Nature Communications Nature communications, vol 12, iss 1 |
| ISSN: | 2041-1723 |
| Popis: | 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. Enhancers for endodermal organs are primed at the chromatin level prior to lineage induction by FOXA pioneer transcription factors; how pervasive this is, is not well known. Here the authors show that only a small subset of organ-specific enhancers are bound and primed by FOXA prior to lineage induction, whereas the majority do not undergo chromatin priming and engage FOXA upon lineage induction. |
| Databáze: | OpenAIRE |
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