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Foxp transcription factors suppress a non-pulmonary gene expression program to permit proper lung development

Shanru Li1, Michael Morley1, MinMin Lu2

  • 1Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA 19104, United States; Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, United States.

Developmental Biology
|June 26, 2016
PubMed

Insights

Forkhead box protein (Foxp1/2/4) transcription factors are crucial for lung development. Their absence in the anterior foregut endoderm disrupts lung lineage commitment by allowing non-pulmonary genes to activate.

Area of Science:

  • Developmental Biology
  • Gene Regulation
  • Molecular Biology

Background:

  • Tissue-specific gene expression is tightly regulated by inhibitory mechanisms that are not fully understood.
  • Forkhead box protein (Foxp) transcription factors, including Foxp1, Foxp2, and Foxp4, are known to repress gene expression and play roles in endoderm development.

Purpose of the Study:

  • To investigate the role of Foxp1/2/4 transcription factors in lung endoderm lineage commitment and development.
  • To elucidate the inhibitory mechanisms underlying tissue-specific gene expression in the developing lung.

Main Methods:

  • Analysis of anterior foregut endoderm development in mice lacking all three Foxp1/2/4 family members.
  • Gene expression profiling of Foxp1/2/4 deficient lungs to identify dysregulated transcriptional regulators.
  • Chromatin immunoprecipitation (ChIP) assays to determine direct binding of Foxp1 to target gene regulatory regions.

Main Results:

  • Combined loss of Foxp1/2/4 results in a failure of lung endoderm lineage commitment and subsequent development.
  • Foxp1/2/4 deficient lungs exhibit ectopic expression of non-pulmonary transcriptional regulators (e.g., Pax2, Pax8, Pax9, Hoxa9-13 cluster).
  • This ectopic expression is associated with decreased expression of essential lung-specific transcription factors (e.g., Nkx2-1, Sox2, Sox9).
  • Foxp1 directly binds to regulatory sites within the Hoxa9-13 cluster, indicating a direct repression mechanism.

Conclusions:

  • Foxp1/2/4 transcription factors are essential for promoting lung endoderm development.
  • They function by actively repressing the expression of non-pulmonary transcription factors, thereby ensuring proper lung lineage commitment.

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