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Molecular and Cellular Biology, April 2006, p. 2901-2912, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.2901-2912.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Permissive Effects of Oxygen on Cyclic AMP and Interleukin-1 Stimulation of Surfactant Protein A Gene Expression Are Mediated by Epigenetic Mechanisms

Departments of Biochemistry and Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038

Received 9 May 2005/ Returned for modification 17 June 2005/ Accepted 17 January 2006

Surfactant protein A (SP-A) is important for immune defense within the alveolus. Cyclic AMP (cAMP) stimulation of SP-A expression in lung type II cells is O₂ dependent and mediated by increased phosphorylation and binding of thyroid transcription factor 1 (TTF-1) to an upstream response element (TTF-1-binding element [TBE]). Interleukin-1 (IL-1) stimulation of SP-A expression is mediated by NF-B (p65/p50) activation and increased binding to the TBE. In this study, we found that O₂ also was permissive for IL-1 induction of SP-A expression and for cAMP and IL-1 stimulation of type II cell nuclear protein binding to the TBE. Using chromatin immunoprecipitation, we observed that when type II cells were cultured in 20% O₂, cAMP and IL-1 stimulated the recruitment of TTF-1, p65, CBP, and steroid receptor coactivator 1 to the TBE region of the SP-A promoter and increased local acetylation of histone H3; these effects were prevented by hypoxia. Hypoxia markedly reduced global levels of CBP and acetylated histone H3 and increased the expression of histone deacetylases. Furthermore, hypoxia caused a global increase in histone H3 dimethylated on Lys9 and increased the association of dimethyl histone H3 with the SP-A promoter. These results, together with findings that the histone deacetylase inhibitor trichostatin A and the methyltransferase inhibitor 5'-deoxy(5'-methylthio)adenosine markedly enhanced SP-A expression in lung type II cells, suggest that increased O₂ availability to type II cells late in gestation causes epigenetic changes that permit access of TTF-1 and NF-B to the SP-A promoter. The binding of these transcription factors facilitates the recruitment of coactivators, resulting in the further opening of the chromatin structure and activation of SP-A transcription.

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