Permissive effects of oxygen on cyclic AMP and interleukin-1 stimulation of surfactant protein A gene expression are mediated by epigenetic mechanisms

Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA.
Molecular and Cellular Biology (Impact Factor: 5.04). 05/2006; 26(8):2901-12. DOI: 10.1128/MCB.26.8.2901-2912.2006
Source: PubMed

ABSTRACT 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 O(2) 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-kappaB (p65/p50) activation and increased binding to the TBE. In this study, we found that O(2) 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% O(2), 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 O(2) availability to type II cells late in gestation causes epigenetic changes that permit access of TTF-1 and NF-kappaB 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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Available from: Kazi Islam, Mar 11, 2014
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    • "The centralized homeodomain is known to bind to other transcription factors, including retinoic acid receptors (RARs) (Yan et al., 2001), zinc finger GATA transcription-6 (GATA-6) (Liu et al., 2002; Weidenfeld et al., 2002), and nuclear factor of activated T cells (NFAT) (Dave et al., 2004). Finally, the COOH-terminus functionally interacts with the DNA repair protein thymine DNA glycosylase (TDG) (Missero et al., 2001), other transcriptional coactivators such as p300 (Bachurski et al., 2003; Grasberger et al., 2005), SRC-3, SRC-2, BR22 (amino acid 6–206) (Yang et al., 2001; 2003), poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1), PARP-2 (Maeda et al., 2006), and other transcription factors such as nuclear factor κB (NF-κB) (Islam and Mendelson, 2006), signal transducers and activators of transcription 3 (STAT3) (Yan et al., 2002), Drosophila mothers against decapentaplegic 3 (SMAD3) (Li et al., 2002), nuclear factor I (NFI) (Missero et al., 2001), and ezrinradixin-moesin (ERM) (Lin et al., 2006). "
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