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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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Autores principales: Khattar, Divya, Fernandes, Sharlene, Snowball, John, Guo, Minzhe, Gillen, Matthew C, Jain, Suchi Singh, Sinner, Debora, Zacharias, William, Swarr, Daniel T
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9427112/
https://www.ncbi.nlm.nih.gov/pubmed/35976093
http://dx.doi.org/10.7554/eLife.67954
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author Khattar, Divya
Fernandes, Sharlene
Snowball, John
Guo, Minzhe
Gillen, Matthew C
Jain, Suchi Singh
Sinner, Debora
Zacharias, William
Swarr, Daniel T
author_facet Khattar, Divya
Fernandes, Sharlene
Snowball, John
Guo, Minzhe
Gillen, Matthew C
Jain, Suchi Singh
Sinner, Debora
Zacharias, William
Swarr, Daniel T
author_sort Khattar, Divya
collection PubMed
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.
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spelling pubmed-94271122022-08-31 PI3K signaling specifies proximal-distal fate by driving a developmental gene regulatory network in SOX9+ mouse lung progenitors Khattar, Divya Fernandes, Sharlene Snowball, John Guo, Minzhe Gillen, Matthew C Jain, Suchi Singh Sinner, Debora Zacharias, William Swarr, Daniel T eLife Developmental Biology 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. eLife Sciences Publications, Ltd 2022-08-17 /pmc/articles/PMC9427112/ /pubmed/35976093 http://dx.doi.org/10.7554/eLife.67954 Text en © 2022, Khattar, Fernandes et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Developmental Biology
Khattar, Divya
Fernandes, Sharlene
Snowball, John
Guo, Minzhe
Gillen, Matthew C
Jain, Suchi Singh
Sinner, Debora
Zacharias, William
Swarr, Daniel T
PI3K signaling specifies proximal-distal fate by driving a developmental gene regulatory network in SOX9+ mouse lung progenitors
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 Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9427112/
https://www.ncbi.nlm.nih.gov/pubmed/35976093
http://dx.doi.org/10.7554/eLife.67954
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