Cell Reports
Volume 28, Issue 2, 9 July 2019, Pages 382-393.e7
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Article
FOXA2 Is Required for Enhancer Priming during Pancreatic Differentiation

https://doi.org/10.1016/j.celrep.2019.06.034Get rights and content
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Highlights

  • ATAC-seq combined with motif analysis predicts key transcription factor involvement

  • FOXA2 is necessary for efficient formation of human pancreatic progenitor cells

  • Remodeling of chromatin architecture during pancreatic differentiation requires FOXA2

  • FOXA2 is required for H3K4me1 deposition before enhancer activation

Summary

Transcriptional regulatory mechanisms of lineage priming in embryonic development are largely uncharacterized because of the difficulty of isolating transient progenitor populations. Directed differentiation of human pluripotent stem cells (hPSCs) combined with gene editing provides a powerful system to define precise temporal gene requirements for progressive chromatin changes during cell fate transitions. Here, we map the dynamic chromatin landscape associated with sequential stages of pancreatic differentiation from hPSCs. Our analysis of chromatin accessibility dynamics led us to uncover a requirement for FOXA2, known as a pioneer factor, in human pancreas specification not previously shown from mouse knockout studies. FOXA2 knockout hPSCs formed reduced numbers of pancreatic progenitors accompanied by impaired recruitment of GATA6 to pancreatic enhancers. Furthermore, FOXA2 is required for proper chromatin remodeling and H3K4me1 deposition during enhancer priming. This work highlights the power of combining hPSC differentiation, genome editing, and computational genomics for discovering transcriptional mechanisms during development.

Keywords

human pluripotent stem cells
hPSCs
human embryonic stem cells
hESCs
pancreatic progenitors
ATAC-seq and chromatin accessibility
FOXA2
FOXA1
enhancer priming and activation
nucleosome remodeling
PDX1
GATA6

Cited by (0)

5

These authors contributed equally

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Present address: Gladstone Institutes, San Francisco, CA 94158, USA

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Lead Contact