Stat3-Bdnf-TrkB axis promotes alveolar regeneration [ATAC-seq]

Description: Summary from the GEO: "Regenerating new alveolar epithelium is essential for recovery from many lung diseases. This multi-cellular regenerative process occurs when type II alveolar pneumocytes (AT2), with support from mesenchymal niche cells, proliferate to generate more AT2 cells and transdifferentiate in type I pneumocytes. To elucidate how coordinated events between AT2 cells and mesenchyme restore alveolar epithelium we used unbiased genome-wide analysis of chromatin accessibility and gene expression in both cell types following acute lung injury. We observed that chromatin acessability in AT2 cells changes signficantly following acute lung injury. Newly accessible chromatin reveals new STAT3 binding motifs adjacent to genes that regulate essential regenerative pathways in AT2 cells. Restoration of alveolar structures following both sterile and infectious lung injuries was inhibited when STAT3 signaling was lost in AT2 cells. Single-cell transcriptome analysis of regenerating AT2 cells identified brain neurotrophic factor (Bdnf) as the sole STAT3 target gene whose chromatin becomes newly accessible in a regenerating population of AT2 cells. BDNF increased alveolar organoid size and forming efficiency in murine and human models. The receptor for BDNF, TrkB, is uniquely? expressed on mesenchymal alveolar niche cells (MANC). Exposure of BDNF to TrkB increases expression of fibroblast growth factor 7 (Fgf7), an essential regenerative cytokine, in MANCs. Blocking Bdnf signaling with a TrkB receptor antagonist abrogated murine and human alveolar organoid formation. Finally, a small molecule TrkB agonist improved functional and histological outcomes in vivo following sterile and infectious lung injuries. Collectively, these data highlight the biological and therapeutic importance of the Stat3-Bdnf-TrkB axis in orchestrating alveolar epithelial regeneration"

Overall design from the GEO: "3 replicates each of control and injured murine AT2 cells isolated from lungs"

Subject of Study

Mus musculus

Subject(s)

Alveolar Epithelial Cells

Receptor, trkB

STAT3 Transcription Factor

Access via GEO
Narrowpeak files of genome binding/occupancy profiling by high throughput sequencing
Accession #: GSE132534

Access via SRA
ATAC sequencing of 6 samples
Accession #: SRP201087

Access via BioProject
Additional information about overall initiative.
Accession #: PRJNA548319
Access Restrictions: Free to All
Access Instructions: The NCBI Gene Expression Omnibus, SRA, and BioProject databases provide open access to these files.
Associated Publications: Paris AJ, Hayer KE, Oved JH, et al. STAT3-BDNF-TrkB signalling promotes alveolar epithelial regeneration after lung injury. Nat Cell Biol. 2020;22(10):1197-1210.
Data Type: Genomic
Equipment Used: Illumina HiSeq 4000
High throughput gene sequencing system
Software Used: SRA Toolkit
The NCBI SRA Toolkit enables reading ("dumping") of sequencing files from the SRA database and writing ("loading") files into the .sra format.
Dataset Format(s): SRA, gzip, NARROWPEAK
Dataset Size: 3.1 MB (NARROWPEAK), 22.3 Gb (SRA)

Data Catalog Record Updated: 2023-12-07