How lung specific transcription factors interact with chromatin remodeling factors to regulate the lung epigenome in both the developing and repairing adult lung is poorly understood. Our previous work has identified the Foxp1/2/4 family of forkhead transcription factors as critical regulators of lung gene transcription. We have recently demonstrated that Foxp1/2/4 physically interact with components of the NuRD chromatin remodeling complex to control lung epithelial gene transcription and the injury response after hyperoxic lung injury. The NuRD complex contains histone deacetylases 1 and 2 (Hdac1 and Hdac2) as its core deacetylase activity. Hdacs function by acetylating histones which causes a relaxation of chromatin structure and increased transcriptional activity. Hdacs can also deacetylate other proteins including transcription factors. Hdac function is counterbalanced by acetylatransferases including p300 and CBP. We have begun to explore the importance of Hdac mediated chromatin remodeling complexes by inactivating Hdac1 and Hdac2 in the developing and adult lung epithelium. Complete loss of Hdac1/2 causes severe defects in early proximal airway epithelial development including decreased maintenance of Sox2+ proximal progenitors accompanied by an increase in apoptosis. A loss of Foxp1 and Foxp4, which interact with Hdac1/2 containing complexes, also results in severe defects in proximal airway epithelial development. Sox2+ proximal progenitors are specified normally in Foxp1/4 DKO mutants but their ability to differentiate into secretory and neuroendocrine cell lineages in the proximal airways is severely compromised. Both microarray and ChIP-seq analysis demonstrates that Foxp1 and Foxp4 regulate a critical network of genes required for secretory cell differentiation in proximal airway epithelium, in particular SPDEF, a master regulator of the goblet cell lineage. The similarities in phenotypes between Hdac1/2 and Foxp1/4 mutants along with the biochemical interaction between these factors suggests that Foxp1/4 function is regulated, at least in part, through interactions with Hdac1/2 containing chromatin remodeling complexes and that together these factors orchestrate proximal airway epithelial differentiation and regeneration. Given the reported association between Hdac2 and COPD as well as the fact that many of the genes regulated by Foxp1/4 are also associated with asthma, COPD, or lung cancer, a better understanding of how Foxp1/2/4 and Hdac1/2 functionally interact to regulate differentiation and regeneration of the secretory cell lineage in the lung will provide important insight into multiple human lung diseases.

Public Health Relevance

Epigenetic mechanisms are thought to regulate various aspects of development and tissue repair. However, little is understood how such pathways regulate lung development and adult epithelial regeneration especially in the setting of lung disease. Hdac2 has been associated with chronic obstructive pulmonary disease but little is understood about the causative role its plays in disease instigation or progression. Hdac's and HAT proteins regulate the balance of histone and transcription factor acetylation and can be targeted by small molecule inhibitors, some of which are already in clinical trials for cancer. Given the dramatic effect that Hdac1/2 have on lung progenitor development and adult regeneration from our preliminary work, our continued studies into how acetylation changes affect the epigenetic mechanisms that regulate lung development and regeneration will have a profound impact on development of future therapies for human lung disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Blaisdell, Carol J
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Li, Shanru; Morley, Michael; Lu, MinMin et al. (2016) Foxp transcription factors suppress a non-pulmonary gene expression program to permit proper lung development. Dev Biol 416:338-46
Li, Shanru; Koziol-White, Cynthia; Jude, Joseph et al. (2016) Epithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsiveness. J Clin Invest 126:1978-82
Spaeth, Jason M; Hunter, Chad S; Bonatakis, Lauren et al. (2015) The FOXP1, FOXP2 and FOXP4 transcription factors are required for islet alpha cell proliferation and function in mice. Diabetologia 58:1836-44
Snitow, Melinda E; Li, Shanru; Morley, Michael P et al. (2015) Ezh2 represses the basal cell lineage during lung endoderm development. Development 142:108-17
Herriges, Michael; Morrisey, Edward E (2014) Lung development: orchestrating the generation and regeneration of a complex organ. Development 141:502-13
Hogan, Brigid L M; Barkauskas, Christina E; Chapman, Harold A et al. (2014) Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell 15:123-38
Wang, Yi; Tian, Ying; Morley, Michael P et al. (2013) Development and regeneration of Sox2+ endoderm progenitors are regulated by a Hdac1/2-Bmp4/Rb1 regulatory pathway. Dev Cell 24:345-58
Li, Shanru; Wang, Yi; Zhang, Yuzhen et al. (2012) Foxp1/4 control epithelial cell fate during lung development and regeneration through regulation of anterior gradient 2. Development 139:2500-9
Wiehagen, Karla R; Corbo-Rodgers, Evann; Li, Shanru et al. (2012) Foxp4 is dispensable for T cell development, but required for robust recall responses. PLoS One 7:e42273
Rousso, David L; Pearson, Caroline Alayne; Gaber, Zachary B et al. (2012) Foxp-mediated suppression of N-cadherin regulates neuroepithelial character and progenitor maintenance in the CNS. Neuron 74:314-30

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