Cargando…
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...
Autores principales: | , , , , , , , , |
---|---|
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 |
_version_ | 1784778825935093760 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9427112 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT khattardivya pi3ksignalingspecifiesproximaldistalfatebydrivingadevelopmentalgeneregulatorynetworkinsox9mouselungprogenitors AT fernandessharlene pi3ksignalingspecifiesproximaldistalfatebydrivingadevelopmentalgeneregulatorynetworkinsox9mouselungprogenitors AT snowballjohn pi3ksignalingspecifiesproximaldistalfatebydrivingadevelopmentalgeneregulatorynetworkinsox9mouselungprogenitors AT guominzhe pi3ksignalingspecifiesproximaldistalfatebydrivingadevelopmentalgeneregulatorynetworkinsox9mouselungprogenitors AT gillenmatthewc pi3ksignalingspecifiesproximaldistalfatebydrivingadevelopmentalgeneregulatorynetworkinsox9mouselungprogenitors AT jainsuchisingh pi3ksignalingspecifiesproximaldistalfatebydrivingadevelopmentalgeneregulatorynetworkinsox9mouselungprogenitors AT sinnerdebora pi3ksignalingspecifiesproximaldistalfatebydrivingadevelopmentalgeneregulatorynetworkinsox9mouselungprogenitors AT zachariaswilliam pi3ksignalingspecifiesproximaldistalfatebydrivingadevelopmentalgeneregulatorynetworkinsox9mouselungprogenitors AT swarrdanielt pi3ksignalingspecifiesproximaldistalfatebydrivingadevelopmentalgeneregulatorynetworkinsox9mouselungprogenitors |