PI3K signaling specifies proximal-distal fate by driving a developmental gene regulatory network in SOX9+ mouse lung progenitors
The tips of the developing respiratory buds are home to important progenitor cells marked by the expression of SOX9 and ID2. Early in embryonic development (prior to E13.5), SOX9+progenitors are multipotent, generating both airway and alveolar epithelium, but are selective progenitors of alveolar ep...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/67954 |
| _version_ | 1797998209719599104 |
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| author | Divya Khattar Sharlene Fernandes John Snowball Minzhe Guo Matthew C Gillen Suchi Singh Jain Debora Sinner William Zacharias Daniel T Swarr |
| author_facet | Divya Khattar Sharlene Fernandes John Snowball Minzhe Guo Matthew C Gillen Suchi Singh Jain Debora Sinner William Zacharias Daniel T Swarr |
| author_sort | Divya Khattar |
| collection | DOAJ |
| description | The tips of the developing respiratory buds are home to important progenitor cells marked by the expression of SOX9 and ID2. Early in embryonic development (prior to E13.5), SOX9+progenitors are multipotent, generating both airway and alveolar epithelium, but are selective progenitors of alveolar epithelial cells later in development. Transcription factors, including Sox9, Etv5, Irx, Mycn, and Foxp1/2 interact in complex gene regulatory networks to control proliferation and differentiation of SOX9+progenitors. Molecular mechanisms by which these transcription factors and other signaling pathways control chromatin state to establish and maintain cell-type identity are not well-defined. Herein, we analyze paired gene expression (RNA-Seq) and chromatin accessibility (ATAC-Seq) data from SOX9+ epithelial progenitor cells (EPCs) during embryonic development in Mus musculus. Widespread changes in chromatin accessibility were observed between E11.5 and E16.5, particularly at distal cis-regulatory elements (e.g. enhancers). Gene regulatory network (GRN) inference identified a common SOX9+ progenitor GRN, implicating phosphoinositide 3-kinase (PI3K) signaling in the developmental regulation of SOX9+ progenitor cells. Consistent with this model, conditional ablation of PI3K signaling in the developing lung epithelium in mouse resulted in an expansion of the SOX9+ EPC population and impaired airway epithelial cell differentiation. These data demonstrate that PI3K signaling is required for epithelial patterning during lung organogenesis, and emphasize the combinatorial power of paired RNA and ATAC seq in defining regulatory networks in development. |
| first_indexed | 2024-04-11T10:45:00Z |
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| id | doaj.art-e9c5c9cb659a4f77ba59f7cf9e6922dd |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:45:00Z |
| publishDate | 2022-08-01 |
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| spelling | doaj.art-e9c5c9cb659a4f77ba59f7cf9e6922dd2022-12-22T04:29:05ZengeLife Sciences Publications LtdeLife2050-084X2022-08-011110.7554/eLife.67954PI3K signaling specifies proximal-distal fate by driving a developmental gene regulatory network in SOX9+ mouse lung progenitorsDivya Khattar0Sharlene Fernandes1John Snowball2Minzhe Guo3Matthew C Gillen4Suchi Singh Jain5Debora Sinner6https://orcid.org/0000-0002-0704-5223William Zacharias7https://orcid.org/0000-0002-2643-0610Daniel T Swarr8https://orcid.org/0000-0002-7305-0442Department of Pediatrics, University of Cincinnati, Cincinnati, United StatesPerinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States; Division of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Winston-Salem, United StatesPerinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States; Division of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Winston-Salem, United StatesPerinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States; Division of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Winston-Salem, United StatesDepartment of Pediatrics, University of Cincinnati, Cincinnati, United StatesPerinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States; Wake Forest University, Winston-Salem, United StatesPerinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States; Division of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Winston-Salem, United States; Department of Pediatrics, University of Cincinnati, Cincinnati, United StatesPerinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States; Division of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Winston-Salem, United States; Department of Medicine, University of Cincinnati, Cincinnati, United StatesDepartment of Pediatrics, University of Cincinnati, Cincinnati, United States; Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States; Division of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Winston-Salem, United States; Department of Pediatrics, University of Cincinnati, Cincinnati, United StatesThe tips of the developing respiratory buds are home to important progenitor cells marked by the expression of SOX9 and ID2. Early in embryonic development (prior to E13.5), SOX9+progenitors are multipotent, generating both airway and alveolar epithelium, but are selective progenitors of alveolar epithelial cells later in development. Transcription factors, including Sox9, Etv5, Irx, Mycn, and Foxp1/2 interact in complex gene regulatory networks to control proliferation and differentiation of SOX9+progenitors. Molecular mechanisms by which these transcription factors and other signaling pathways control chromatin state to establish and maintain cell-type identity are not well-defined. Herein, we analyze paired gene expression (RNA-Seq) and chromatin accessibility (ATAC-Seq) data from SOX9+ epithelial progenitor cells (EPCs) during embryonic development in Mus musculus. Widespread changes in chromatin accessibility were observed between E11.5 and E16.5, particularly at distal cis-regulatory elements (e.g. enhancers). Gene regulatory network (GRN) inference identified a common SOX9+ progenitor GRN, implicating phosphoinositide 3-kinase (PI3K) signaling in the developmental regulation of SOX9+ progenitor cells. Consistent with this model, conditional ablation of PI3K signaling in the developing lung epithelium in mouse resulted in an expansion of the SOX9+ EPC population and impaired airway epithelial cell differentiation. These data demonstrate that PI3K signaling is required for epithelial patterning during lung organogenesis, and emphasize the combinatorial power of paired RNA and ATAC seq in defining regulatory networks in development.https://elifesciences.org/articles/67954chromatin accessibilitylung developmentATAC-Seqlung distal tip progenitor cellsepigenomics |
| spellingShingle | Divya Khattar Sharlene Fernandes John Snowball Minzhe Guo Matthew C Gillen Suchi Singh Jain Debora Sinner William Zacharias Daniel T Swarr PI3K signaling specifies proximal-distal fate by driving a developmental gene regulatory network in SOX9+ mouse lung progenitors eLife chromatin accessibility lung development ATAC-Seq lung distal tip progenitor cells epigenomics |
| title | PI3K signaling specifies proximal-distal fate by driving a developmental gene regulatory network in SOX9+ mouse lung progenitors |
| title_full | PI3K signaling specifies proximal-distal fate by driving a developmental gene regulatory network in SOX9+ mouse lung progenitors |
| title_fullStr | PI3K signaling specifies proximal-distal fate by driving a developmental gene regulatory network in SOX9+ mouse lung progenitors |
| title_full_unstemmed | PI3K signaling specifies proximal-distal fate by driving a developmental gene regulatory network in SOX9+ mouse lung progenitors |
| title_short | PI3K signaling specifies proximal-distal fate by driving a developmental gene regulatory network in SOX9+ mouse lung progenitors |
| title_sort | pi3k signaling specifies proximal distal fate by driving a developmental gene regulatory network in sox9 mouse lung progenitors |
| topic | chromatin accessibility lung development ATAC-Seq lung distal tip progenitor cells epigenomics |
| url | https://elifesciences.org/articles/67954 |
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