The Transcription Factors Grainyhead-like 2 and NK2-Homeobox 1 Form a Regulatory Loop That Coordinates Lung Epithelial Cell Morphogenesis and Differentiation
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The Grainyhead family of transcription factors controls morphogenesis and differentiation of epithelial cell layers in multicellular organisms by regulating cell junction- and proliferation-related genes. Grainyhead-like 2 (Grhl2) is expressed in developing mouse lung epithelium and is required for normal lung organogenesis. The specific epithelial cells expressing Grhl2 and the genes regulated by Grhl2 in normal lungs are mostly unknown. In these studies we identified the NK2-homeobox 1 transcription factor (Nkx2-1) as a direct transcriptional target of Grhl2. By binding and transcriptional assays and by confocal microscopy we showed that these two transcription factors form a positive feedback loop in vivo and in cell lines and are co-expressed in lung bronchiolar and alveolar type II cells. The morphological changes observed in flattening lung alveolar type II cells in culture are associated with down-regulation of Grhl2 and Nkx2-1. Reduction of Grhl2 in lung epithelial cell lines results in lower expression levels of Nkx2-1 and of known Grhl2 target genes. By microarray analysis we identified that in addition to Cadherin1 and Claudin4, Grhl2 regulates other cell interaction genes such as semaphorins and their receptors, which also play a functional role in developing lung epithelium. Impaired collective cell migration observed in Grhl2 knockdown cell monolayers is associated with reduced expression of these genes and may contribute to the altered epithelial phenotype reported in Grhl2 mutant mice. Thus, Grhl2 functions at the nexus of a novel regulatory network, connecting lung epithelial cell identity, migration, and cell-cell interactions.
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Additional file 9 of GRHL2-controlled gene expression networks in luminal breast cancer
Wang, Z., Coban, B., Wu, H., Chouaref, J., Daxinger, L., Paulsen, M. T., Ljungman, M. E., Smid, M., Martens, J. W. M., & Danen, E. H. J. (2024) · Figshare · doi:10.6084/m9.figshare.26563375
Additional file 8 of GRHL2-controlled gene expression networks in luminal breast cancer
Wang, Z., Coban, B., Wu, H., Chouaref, J., Daxinger, L., Paulsen, M. T., Ljungman, M. E., Smid, M., Martens, J. W. M., & Danen, E. H. J. (2024) · Figshare · doi:10.6084/m9.figshare.26563372
Additional file 4 of GRHL2-controlled gene expression networks in luminal breast cancer
Wang, Z., Coban, B., Wu, H., Chouaref, J., Daxinger, L., Paulsen, M. T., Ljungman, M. E., Smid, M., Martens, J. W. M., & Danen, E. H. J. (2024) · Figshare · doi:10.6084/m9.figshare.26563360
Additional file 3 of GRHL2-controlled gene expression networks in luminal breast cancer
Wang, Z., Coban, B., Wu, H., Chouaref, J., Daxinger, L., Paulsen, M. T., Ljungman, M. E., Smid, M., Martens, J. W. M., & Danen, E. H. J. (2024) · Figshare · doi:10.6084/m9.figshare.26563357
Additional file 6 of GRHL2-controlled gene expression networks in luminal breast cancer
Wang, Z., Coban, B., Wu, H., Chouaref, J., Daxinger, L., Paulsen, M. T., Ljungman, M. E., Smid, M., Martens, J. W. M., & Danen, E. H. J. (2024) · Figshare · doi:10.6084/m9.figshare.26563366
Additional file 5 of GRHL2-controlled gene expression networks in luminal breast cancer
Wang, Z., Coban, B., Wu, H., Chouaref, J., Daxinger, L., Paulsen, M. T., Ljungman, M. E., Smid, M., Martens, J. W. M., & Danen, E. H. J. (2024) · Figshare · doi:10.6084/m9.figshare.26563363
Additional file 7 of GRHL2-controlled gene expression networks in luminal breast cancer
Wang, Z., Coban, B., Wu, H., Chouaref, J., Daxinger, L., Paulsen, M. T., Ljungman, M. E., Smid, M., Martens, J. W. M., & Danen, E. H. J. (2024) · Figshare · doi:10.6084/m9.figshare.26563369
Additional file 2 of GRHL2-controlled gene expression networks in luminal breast cancer
Wang, Z., Coban, B., Wu, H., Chouaref, J., Daxinger, L., Paulsen, M. T., Ljungman, M. E., Smid, M., Martens, J. W. M., & Danen, E. H. J. (2024) · Figshare · doi:10.6084/m9.figshare.26563354
Wang, Y., Li, Y., Bao, L., Lu, J., Li, X., Fu, Y., Zhang, D., & Li, H. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1881734
- Authors
- Varma, S., Cao, Y., Tagne, J.-B., Lakshminarayanan, M., Li, J., Friedman, T. B., Morell, R. J., Warburton, D., Kotton, D. N., & Ramirez, M. I.
- Affiliations
- Boston University (US)
- National Institutes of Health (US)
- University of Southern California (US)
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 287
- Issue
- 44
- Pages
- 37282-37295
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3481326
- OpenAlex
- W1971001507
- Cited by
- 79
- References
- 64
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 7 · 2023: 3 · 2022: 5 · 2021: 3 · 2020: 6 · 2019: 2 · 2018: 6 · 2017: 12 · 2016: 10 · 2015: 7 · 2014: 5 · 2013: 6 · 2012: 2
- FWCI
- 2.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (P01-HL-47049, R01HL083034, R01 HL0833034, P01HL047049)
- National Institute on Deafness and Other Communication Disorders (DC000039‐15)
- National Institute of General Medical Sciences (R01GM096195)
- National Center for Research Resources (UL1RR025771)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Neonatal Respiratory Health Research
- Keywords
- GRHL2, TTF-1, transcriptional feedback loop, alveolar type II cells, cell-cell interactions, collective cell migration, semaphorins, semaphorin receptors, lung organogenesis, epithelial differentiation
- MeSH terms
- Thyroid Nuclear Factor 1, Animals, Cell Differentiation, Cell Line, Cell Movement, Lung, Morphogenesis, Nuclear Proteins, Phalloidine, Phenotype, Promoter Regions, Genetic, Protein Binding, Transcription Factors, Transcriptional Activation, Gene Expression, Gene Expression Regulation, Developmental, Chromatin Immunoprecipitation, Cell Shape, Cell Proliferation, Mice, Gene Regulatory Networks, Alveolar Epithelial Cells, Transcriptome
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