Elevated levels of polyamines alter chromatin in murine skin and tumors without global changes in nucleosome acetylation.
Polyamines affect nucleosome oligomerization and DNA conformation in vitro, yet little information exists regarding the influence of naturally synthesized polyamines on mammalian chromatin. Capitalizing on the relative inefficiency of a moderate ionic strength extraction buffer to dissociate histones, we obtained evidence of altered chromatin in transgenic mice that overexpress ornithine decarboxylase (ODC), which catalyzes polyamine synthesis. Dissociation of histones from chromatin in ODC transgenic mouse skin, as well as in tumors that develop spontaneously in ODC/Ras bigenic mice, is dramatically reduced relative to normal littermate skin. This could reflect tighter tethering of nucleosomes to DNA or a more compacted chromatin structure due to elevated intracellular concentrations of polyamines since this effect is reversible upon treatment with alpha-difluoromethylornithine (DFMO), a specific inhibitor of ODC enzymatic activity. Impeded release of nonhistone chromatin proteins HP-1beta and nucleophosmin, but not Lamin B, HDAC-1, HMGB, HMGN2, or HMGA1, suggests that polyamines exert selective effects on specific chromatin protein complexes. Moreover, overall acetylation, as well as specific methylation, of nucleosomes in ODC mice is unaffected, implying that access by histone modifying enzymes is not generally restricted. The abnormal chromatin environment fostered by elevated levels of polyamines may be a necessary prerequisite for epithelial tumor growth and maintenance.
Hobbs
Cheryl A
CA
Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA.
Paul
Barry A
BA
Gilmour
Susan K
SK
D000107:Acetylation; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D000518:Eflornithine / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D011905:Genes, ras / Q000502:physiology; D024003:HMGA Proteins / Q000378:metabolism; D024002:HMGB Proteins / Q000378:metabolism; D024242:HMGN2 Protein / Q000378:metabolism; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D034921:Lamin Type B / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism; D000090243:Nucleophosmin; D009707:Nucleosomes / Q000378:metabolism*; D009955:Ornithine Decarboxylase / Q000235:genetics; D011073:Polyamines / Q000378:metabolism*; D012867:Skin / Q000201:enzymology* / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism*
D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D024003:HMGA Proteins; D024002:HMGB Proteins; D024242:HMGN2 Protein; D034921:Lamin Type B; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D009707:Nucleosomes; D011073:Polyamines; D000090266:Chromobox Protein Homolog 5; D000090243:Nucleophosmin; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D009955:Ornithine Decarboxylase; D000518:Eflornithine