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: 4.78). 05/2006; 26(8):2901-12. DOI: 10.1128/MCB.26.8.2901-2912.2006
Source: PubMed


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-κB (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-κB 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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    • "revealed that amongst the seven, KIAA1324, NET1, NTN3, RPL10 and TFPI2 were epigenetically regulated through DNA methylation. In the remaining two, SFTPA1 was epigenetically regulated [56-58]. However, the experimental evidence was lacking the epigenetic related data for CRISP3. "
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