FOXA2 Is Required for Enhancer Priming during Pancreatic Differentiation
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 power...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-07-01
|
| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719308009 |
| _version_ | 1818947583090884608 |
|---|---|
| author | Kihyun Lee Hyunwoo Cho Robert W. Rickert Qing V. Li Julian Pulecio Christina S. Leslie Danwei Huangfu |
| author_facet | Kihyun Lee Hyunwoo Cho Robert W. Rickert Qing V. Li Julian Pulecio Christina S. Leslie Danwei Huangfu |
| author_sort | Kihyun Lee |
| collection | DOAJ |
| description | 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. : Lee et al. use ATAC-seq to identify key transcriptional factors involved in human pancreatic differentiation. FOXA2 knockout human pluripotent stem cells showed impaired differentiation to pancreatic progenitors, a phenotype not observed in Foxa2 conditional knockout mice. Furthermore, FOXA2 is required for proper chromatin remodeling and H3K4me1 deposition during enhancer priming. 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 |
| first_indexed | 2024-12-20T08:33:12Z |
| format | Article |
| id | doaj.art-3ae9bdac9b504487a47ec8680a20e805 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-20T08:33:12Z |
| publishDate | 2019-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-3ae9bdac9b504487a47ec8680a20e8052022-12-21T19:46:38ZengElsevierCell Reports2211-12472019-07-01282382393.e7FOXA2 Is Required for Enhancer Priming during Pancreatic DifferentiationKihyun Lee0Hyunwoo Cho1Robert W. Rickert2Qing V. Li3Julian Pulecio4Christina S. Leslie5Danwei Huangfu6Developmental 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, USAWeill Graduate School of Medical Sciences at Cornell University, New York, NY 10065, USA; Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USADevelopmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USADevelopmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USADevelopmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USAComputational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Corresponding authorDevelopmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Corresponding authorSummary: 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. : Lee et al. use ATAC-seq to identify key transcriptional factors involved in human pancreatic differentiation. FOXA2 knockout human pluripotent stem cells showed impaired differentiation to pancreatic progenitors, a phenotype not observed in Foxa2 conditional knockout mice. Furthermore, FOXA2 is required for proper chromatin remodeling and H3K4me1 deposition during enhancer priming. 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, GATA6http://www.sciencedirect.com/science/article/pii/S2211124719308009 |
| spellingShingle | Kihyun Lee Hyunwoo Cho Robert W. Rickert Qing V. Li Julian Pulecio Christina S. Leslie Danwei Huangfu FOXA2 Is Required for Enhancer Priming during Pancreatic Differentiation Cell Reports |
| title | FOXA2 Is Required for Enhancer Priming during Pancreatic Differentiation |
| title_full | FOXA2 Is Required for Enhancer Priming during Pancreatic Differentiation |
| title_fullStr | FOXA2 Is Required for Enhancer Priming during Pancreatic Differentiation |
| title_full_unstemmed | FOXA2 Is Required for Enhancer Priming during Pancreatic Differentiation |
| title_short | FOXA2 Is Required for Enhancer Priming during Pancreatic Differentiation |
| title_sort | foxa2 is required for enhancer priming during pancreatic differentiation |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719308009 |
| work_keys_str_mv | AT kihyunlee foxa2isrequiredforenhancerprimingduringpancreaticdifferentiation AT hyunwoocho foxa2isrequiredforenhancerprimingduringpancreaticdifferentiation AT robertwrickert foxa2isrequiredforenhancerprimingduringpancreaticdifferentiation AT qingvli foxa2isrequiredforenhancerprimingduringpancreaticdifferentiation AT julianpulecio foxa2isrequiredforenhancerprimingduringpancreaticdifferentiation AT christinasleslie foxa2isrequiredforenhancerprimingduringpancreaticdifferentiation AT danweihuangfu foxa2isrequiredforenhancerprimingduringpancreaticdifferentiation |