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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL071589-10
Application #
8235445
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Blaisdell, Carol J
Project Start
2002-12-09
Project End
2016-02-29
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
10
Fiscal Year
2012
Total Cost
$359,786
Indirect Cost
$134,920
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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