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Efficient Differentiation of Pluripotent Stem Cells to NKX6-1+ Pancreatic Progenitors
Published on: March 7, 2017
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FOXA2 Is Required for Enhancer Priming during Pancreatic Differentiation.
Kihyun Lee1, Hyunwoo Cho2, Robert W Rickert3
1Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Graduate School of Medical Sciences at Cornell University, New York, NY 10065, USA.
Cell Reports
|July 11, 2019
Summary
This study reveals FOXA2 is crucial for human pancreas development, guiding chromatin changes and progenitor formation. FOXA2 (forkhead box A2) is essential for recruiting other factors to pancreatic enhancers.
Area of Science:
- Developmental Biology
- Stem Cell Biology
- Genomics
Background:
- Transcriptional regulation of lineage priming during embryonic development is poorly understood.
- Studying transient progenitor populations is challenging.
- Human pluripotent stem cells (hPSCs) offer a model for studying cell fate transitions.
Purpose of the Study:
- To define temporal gene requirements for chromatin changes during pancreatic cell fate transitions.
- To map the dynamic chromatin landscape during pancreatic differentiation from hPSCs.
- To uncover the role of pioneer factors in human pancreas specification.
Main Methods:
- Directed differentiation of hPSCs.
- CRISPR-Cas9 gene editing to create FOXA2 knockout hPSCs.
- Chromatin accessibility assays (ATAC-seq).
- Computational genomics analysis.
Main Results:
- FOXA2 is essential for human pancreas specification, a role not evident in mouse models.
- FOXA2 knockout hPSCs show reduced pancreatic progenitor numbers.
- FOXA2 is required for GATA6 recruitment to pancreatic enhancers and proper chromatin remodeling.
- FOXA2 influences H3K4me1 deposition at enhancers during priming.
Conclusions:
- FOXA2 acts as a critical pioneer factor in human pancreatic development.
- Combining hPSC differentiation, gene editing, and genomics is powerful for discovering developmental mechanisms.
- This study provides new insights into the transcriptional control of pancreas organogenesis.
Keywords:
ATAC-seq and chromatin accessibilityFOXA1FOXA2GATA6PDX1enhancer priming and activationhESCshPSCshuman embryonic stem cellshuman pluripotent stem cellsnucleosome remodelingpancreatic progenitorsMore Related Videos
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