Surfactant protein A (SP-A) is developmentally regulated in fetal lung type II cells in concert with surfactant phospholipid synthesis and, thus, serves as an excellent marker of type II cell differentiation and surfactant production. SP-A, a C-type lectin, plays an important role in immune defense within the lung alveolus and may serve as a fetal signal in the initiation of labor. SP-A expression in cultured human fetal type II cells is markedly stimulated by cAMP and by interleukin-1 (IL-1), and is inhibited by glucocorticoids. cAMP stimulation of SP-A expression is O2-dependent and mediated by binding of estrogen-related receptor ( (ERR(), a complex of thyroid transcription factor-1 (TTF-1/Nkx2.1) and nuclear factor (B (NF-(B), upstream stimulatory factors (USFs) 1 and 2, and Sp1 to critical response elements upstream of the SP-A gene. The stimulatory effects of cAMP and IL-1, permissive effects of O2 and inhibitory effects of glucocorticoids on SP-A expression are associated with changes in phosphorylation, DNA-binding and transcriptional activity of TTF-1 and NF-(B. Increased TTF-1/NF-(B binding alters recruitment to the SP-A promoter of coactivators and corepressors eliciting modifications in histone phosphorylation, acetylation and methylation that likely cause profound changes in chromatin structure. In the proposed research, we will utilize fetal lung tissues from humans and mice to further define the underlying biochemical and molecular mechanisms for epigenetic and genetic changes associated with developmental, hormonal and O2 regulation of SP-A gene expression in fetal lung. Using chromatin immunoprecipitation, we will analyze temporal changes in in vivo recruitment of key transcription factors and coregulators to the SP-A promoter in lung tissues and cells of fetal and neonatal mice and in human fetal lung explants and epithelial cells during type II cell differentiation in culture. This will be correlated with local changes in histone modification, DNA methylation, and DNaseI hypersensitive sites, to assess changes in chromatin structure. The histone- and DNA-modifying enzymes that bind to the SP-A promoter in type II cells and mediate developmental-, hormonal- and O2-regulated changes in chromatin structure also will be defined;their functional importance will be assessed using RNAi-mediated knockdown. The potential roles of hypoxia-induced transcription factors as mediators of the effects of O2 tension on SP-A expression also will be considered.
Pulmonary surfactant, a developmentally regulated lipoprotein synthesized in alveolar type II cells, reduces surface tension within the lung alveolus and is essential for normal breathing. Inadequate surfactant production by lungs of prematurely born infants can result in respiratory distress syndrome (RDS), the leading cause of neonatal morbidity and mortality in the U.S. To define the basic mechanisms involved in type II cell-specific, developmental and hormonal regulation of surfactant synthesis, we have focused on the gene encoding the major surfactant protein-A, SP-A, which is developmentally regulated in fetal lung in concert with surfactant phospholipid synthesis and serves as an excellent marker of fetal lung maturity. We recently obtained intriguing evidence that augmented SP-A production by the maturing fetal lung may provide a hormonal signal from fetus to mother leading to the initiation of labor. After birth, SP-A serves as an important component of the innate immune system within the lung to protect against invading microorganisms and to modulate inflammation. The studies outlined in this proposal will advance our understanding of the biochemical, genetic and epigenetic mechanisms that mediate the developmental and hormonal regulation of SP-A gene expression in fetal lung, as well as the permissive effects of increased O2 tension. Studies to correlate developmental, hormonal and O2-regulated changes in SP-A expression with binding of key transcription factors and coregulators and the resulting epigenetic marks at the SP-A gene promoter will provide important insight into the molecular events that control expression of this physiologically relevant gene.
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