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PI3K Signaling Specifies Proximal-Distal Fate by Driving a Developmental Gene Regulatory Network in SOX9+ Lung Progenitors

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE188239 | GEO | 2022/08/25

REPOSITORIES: GEO

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PI3K signaling specifies proximal-distal fate by driving a developmental gene regulatory network in SOX9+ mouse lung progenitors.

Project 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.

| S-EPMC9427112 | biostudies-literature

PI3K Signaling Specifies Proximal-Distal Fate by Driving a Developmental Gene Regulatory Network in SOX9+ Lung Progenitors [ATAC-seq]

Project description:In order to understand the epigenetic mechanisms directing development and differentiation of SOX9+ lung epithelial progenitor cells (EPCs), paired RNA-Seq and ATAC-Seq was performed on SOX9+ EPCs sorted using flow cytometry from a Sox9-GFP reporter mouse.

2022-08-25 | GSE188237 | GEO

PI3K Signaling Specifies Proximal-Distal Fate by Driving a Developmental Gene Regulatory Network in SOX9+ Lung Progenitors [RNA-seq]

2022-08-25 | GSE188230 | GEO

PI3K Signaling Specifies Proximal-Distal Fate by Driving a Developmental Gene Regulatory Network in SOX9+ Lung Progenitors

Project description:PI3K Signaling Specifies Proximal-Distal Fate by Driving a Developmental Gene Regulatory Network in SOX9+ Lung Progenitors

| PRJNA777958 | ENA

PI3K Signaling Specifies Proximal-Distal Fate by Driving a Developmental Gene Regulatory Network in SOX9+ Lung Progenitors [RNA-seq]

Project description:PI3K Signaling Specifies Proximal-Distal Fate by Driving a Developmental Gene Regulatory Network in SOX9+ Lung Progenitors [RNA-seq]

| PRJNA777948 | ENA

PI3K Signaling Specifies Proximal-Distal Fate by Driving a Developmental Gene Regulatory Network in SOX9+ Lung Progenitors [ATAC-seq]

Project description:PI3K Signaling Specifies Proximal-Distal Fate by Driving a Developmental Gene Regulatory Network in SOX9+ Lung Progenitors [ATAC-seq]

| PRJNA777957 | ENA

Asymmetric PI3K Signaling Driving Developmental and Regenerative Cell Fate Bifurcation.

Project description:Metazoan sibling cells often diverge in activity and identity, suggesting links between growth signals and cell fate. We show that unequal transduction of nutrient-sensitive PI3K/AKT/mTOR signaling during cell division bifurcates transcriptional networks and fates of kindred cells. A sibling B lymphocyte with stronger signaling, indexed by FoxO1 inactivation and IRF4 induction, undergoes PI3K-driven Pax5 repression and plasma cell determination, while its sibling with weaker PI3K activity renews a memory or germinal center B cell fate. PI3K-driven effector T cell determination silences TCF1 in one sibling cell, while its PI3K-attenuated sibling self-renews in tandem. Prior to bifurcations achieving irreversible plasma or effector cell fate determination, asymmetric signaling during initial divisions specifies a more proliferative, differentiation-prone lymphocyte in tandem with a more quiescent memory cell sibling. By triggering cell division but transmitting unequal intensity between sibling cells, nutrient-sensitive signaling may be a frequent arbiter of cell fate bifurcations during development and repair.

| S-EPMC4685001 | biostudies-literature

Lhx2 specifies regional fate in Emx1 lineage of telencephalic progenitors generating cerebral cortex.

Project description:Cerebral cortex is comprised of regions, including six-layer neocortex and three-layer olfactory cortex, generated by telencephalic progenitors of an Emx1 lineage. The mechanism specifying region-specific subpopulations in this lineage is unknown. We found that the LIM homeodomain transcription factor Lhx2 in mice, expressed in graded levels by progenitors, determines their regional identity and fate decisions to generate neocortex or olfactory cortex. Deletion of Lhx2 with Emx1-cre at embryonic day 10.5 (E10.5) altered the fates of progenitors, causing them to generate three-layer cortex, phenocopying olfactory cortex rather than lateral neocortex. Progenitors did not generate ectopic olfactory cortex following Lhx2 deletion at E11.5. Thus, Lhx2 regulates a regional-fate decision by telencephalic progenitors during a critical period that ends as they differentiate from neuroepithelial cells to neuronogenic radial glia. These findings establish a genetic mechanism for determining regional-fate in the Emx1 lineage of telencephalic progenitors that generate cerebral cortex.

| S-EPMC2897740 | biostudies-literature

Sox9 and Lef1 Regulate the Fate and Behavior of Airway Glandular Progenitors in Response to Injury.

Project description:Cartilaginous airways of larger mammals and the mouse trachea contain at least 3 well-established stem cell compartments, including basal cells of the surface airway epithelium (SAE) and ductal and myoepithelial cells of the submucosal glands (SMG). Here we demonstrate that glandular Sox9-expressing progenitors capable of SAE repair decline with age in mice. Notably, Sox9-lineage glandular progenitors produced basal and ciliated cells in the SAE, but failed to produce secretory cells. Lef1 was required for glandular Sox9 lineage contribution to SAE repair, and its deletion significantly reduced proliferation following injury. By contrast, in vivo deletion of Sox9 enhanced proliferation of progenitors in both the SAE and SMG shortly following injury, but these progenitors failed to proliferate in vitro in the absence of Sox9, similar to that previously shown for Lef1 deletion. In cystic fibrosis ferret airways, Sox9 expression inversely correlated with Ki67 proliferative marker expression in SMG and the SAE. Using in vitro and ex vivo models, we demonstrate that Sox9 is extinguished as glandular progenitors exit ducts and proliferate on the airway surface and that Sox9 is required for migration and proper differentiation of SMG, but not surface airway, progenitors. We propose a model whereby Wnt/Lef1 and Sox9 signals differentially regulate the proliferative and migratory behavior of glandular progenitors, respectively.

| S-EPMC9406614 | biostudies-literature

The early proximal ?? TCR signalosome specifies thymic selection outcome through a quantitative protein interaction network.

Project description:During ?? T cell development, T cell antigen receptor (TCR) engagement transduces biochemical signals through a protein-protein interaction (PPI) network that dictates dichotomous cell fate decisions. It remains unclear how signal specificity is communicated, instructing either positive selection to advance cell differentiation or death by negative selection. Early signal discrimination might occur by PPI signatures differing qualitatively (customized, unique PPI combinations for each signal), quantitatively (graded amounts of a single PPI series), or kinetically (speed of PPI pathway progression). Using a novel PPI network analysis, we found that early TCR-proximal signals distinguishing positive from negative selection appeared to be primarily quantitative in nature. Furthermore, the signal intensity of this PPI network was used to find an antigen dose that caused a classic negative selection ligand to induce positive selection of conventional ?? T cells, suggesting that the quantity of TCR triggering was sufficient to program selection outcome. Because previous work had suggested that positive selection might involve a qualitatively unique signal through CD3?, we reexamined the block in positive selection observed in CD3?0 mice. We found that CD3?0 thymocytes were inhibited but capable of signaling positive selection, generating low numbers of MHC-dependent ?? T cells that expressed diverse TCR repertoires and participated in immune responses against infection. We conclude that the major role for CD3? in positive selection is to quantitatively boost the signal for maximal generation of ?? T cells. Together, these data indicate that a quantitative network signaling mechanism through the early proximal TCR signalosome determines thymic selection outcome.

| S-EPMC7252671 | biostudies-literature

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