AP-1 specifies developmental versus fibrotic extracellular matrix transcriptional programs in the lung

Abstract

Lung function requires an elastic extracellular matrix (ECM). However, the adult lung does not regenerate the elastic architecture established during development, and deposition of fibrous ECM characterizes many lung diseases. We generated a multimodal, single-nuclei atlas across development, homeostasis, aging, and fibrosis to identify lung fibroblast populations, transcriptional programs, and regulatory logic governing these divergent matrix outcomes. We discovered differential AP-1 transcription factor activity orchestrates distinct ECM programs via preferential binding to TPA-responsive elements (TRE) in fibrosis and cAMP-responsive elements (CRE) in development. Antagonizing AP-1 TRE-signaling in lung fibroblasts repressed the fibrotic program and re-engaged a developmental, elastogenic state, and MEK inhibition produced similar transcriptional phenotypes. Pathological fibroblasts in interstitial lung diseases upregulated TRE motif activity, and expression of downstream fibrosis signatures positively correlated with disease severity. These results uncover AP-1 as a critical signaling hub governing lung fibroblast ECM deposition that can potentially be exploited to improve disease outcomes.

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BibTeX RIS

BibTeX

@misc{kaiser2026specifies,
  title = {{AP-1 specifies developmental versus fibrotic extracellular matrix transcriptional programs in the lung}},
  author = {A. M. Kaiser and A. Luo and K. Sivasubramanian and G. Duenas and B. Martin-McNulty and W. Cedron-Craft and J. M. Patino and A. J. Chang and J. Riegler and J. G. Ruby},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.10.750752},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.10.750752v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - AP-1 specifies developmental versus fibrotic extracellular matrix transcriptional programs in the lung
AU  - A. M. Kaiser
AU  - A. Luo
AU  - K. Sivasubramanian
AU  - G. Duenas
AU  - B. Martin-McNulty
AU  - W. Cedron-Craft
AU  - J. M. Patino
AU  - A. J. Chang
AU  - J. Riegler
AU  - J. G. Ruby
PY  - 2026
DA  - 2026/09/10
PB  - bioRxiv
DO  - 10.64898/2026.09.10.750752
UR  - https://www.biorxiv.org/content/10.64898/2026.09.10.750752v1
AB  - Lung function requires an elastic extracellular matrix (ECM). However, the adult lung does not regenerate the elastic architecture established during development, and deposition of fibrous ECM characterizes many lung diseases. We generated a multimodal, single-nuclei atlas across development, homeostasis, aging, and fibrosis to identify lung fibroblast populations, transcriptional programs, and regulatory logic governing these divergent matrix outcomes. We discovered differential AP-1 transcription factor activity orchestrates distinct ECM programs via preferential binding to TPA-responsive elements (TRE) in fibrosis and cAMP-responsive elements (CRE) in development. Antagonizing AP-1 TRE-signaling in lung fibroblasts repressed the fibrotic program and re-engaged a developmental, elastogenic state, and MEK inhibition produced similar transcriptional phenotypes. Pathological fibroblasts in interstitial lung diseases upregulated TRE motif activity, and expression of downstream fibrosis signatures positively correlated with disease severity. These results uncover AP-1 as a critical signaling hub governing lung fibroblast ECM deposition that can potentially be exploited to improve disease outcomes.
ER  -

Abstract

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