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Division of Pharmacology, The Ohio State University College of Pharmacy (J.L.R., H.H., S.F.W., D.G.H.), and the Dorothy M. Davis Heart and Lung Research Institute (D.G.H.), Columbus, Ohio
Engagement of integrin cell adhesion receptors in mouse lung endothelial cells induces global sensitivity of DNA to nuclease digestion, reflecting alterations in chromatin structure. These structural changes may contribute to the antigenotoxic effects of integrin engagement in lung endothelium. Because histone acetylation and poly(ADP-ribosyl)ation modulate chromatin structure, we investigated the effects of 
1 integrin engagement with antibody on these post-translational modifications and the presence of histones at discrete DNA sequences in the mouse lung endothelial cell genome using chromatin immunoprecipitation. Integrin engagement increased acetylation of core histone H3. The presence of acetylated histone H3 at intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) promoters, and a nonpromoter sequence was also increased. As with integrin engagement, the histone deacetylase inhibitor trichostatin A caused global hypersensitivity of DNA to nuclease digestion and induced acetylation of histone H3 and its coimmunoprecipitation with VCAM-1 and ICAM-1 promoters and nonpromoter DNA. In contrast to acetyl-histone H3, the association of linker histone H1 with specific DNA sequences was either reduced or unaffected by integrin engagement and trichostatin A. Although integrin engagement and trichostatin A treatment did not affect histone H1 poly(ADP-ribosyl)ation, deletion of poly(ADP-ribose) polymerase-1 increased core histone H3 acetylation and increased its level at the iNOS promoter while decreasing the amount of histone H1. The results suggest that integrin engagement, as well as trichostatin A and PARP-1 deletion, regulate chromatin structure via core histone H3 acetylation and reduced linker histone H1-DNA association.
Address correspondence to: Dr. Dale G. Hoyt, Division of Pharmacology, The Ohio State University College of Pharmacy, 500 West Twelfth Avenue, Columbus, OH 43210. E-mail: hoyt.27{at}osu.edu
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