Permissive effects of oxygen on cyclic AMP and interleukin-1 stimulation of surfactant protein A gene expression are mediated by epigenetic mechanisms.
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.
Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA.
Kazi Nazrul
KN
Islam
Carole R
CR
Mendelson
D000107:Acetylation / Q000187:drug effects; D050882:CREB-Binding Protein / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D000242:Cyclic AMP / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009924:Organ Culture Techniques; D010100:Oxygen / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D037662:Pulmonary Surfactant-Associated Protein A / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism
D006657:Histones; D007375:Interleukin-1; D016328:NF-kappa B; D037662:Pulmonary Surfactant-Associated Protein A; D012333:RNA, Messenger; D014157:Transcription Factors; D000242:Cyclic AMP; D050882:CREB-Binding Protein; D006655:Histone Deacetylases; D010100:Oxygen