Elevated levels of polyamines alter chromatin in murine skin and tumors without global changes in nucleosome acetylation
Elevated levels of polyamines alter chromatin in murine skin and tumors without global changes in nucleosome acetylation
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DOI：
10.1016/s0014-4827(03)00352-5
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发表时间：
2003-11-01
影响因子：
3.7
通讯作者：
Gilmour, SK
中科院分区：
文献类型：
--
作者：
Hobbs, CA;Paul, BA;Gilmour, SK
多胺在体外影响核小体寡聚化和 DNA 构象，但有关天然合成多胺对哺乳动物染色质影响的信息很少。利用中等离子强度提取缓冲液解离组蛋白的相对低效性，我们获得了过度表达鸟氨酸脱羧酶（ODC）（催化多胺合成）的转基因小鼠中染色质发生改变的证据。与正常同窝小鼠皮肤相比，ODC 转基因小鼠皮肤以及 ODC/Ras 双基因小鼠自发形成的肿瘤中染色质的解离历史显着减少。这可能反映出由于细胞内多胺浓度升高，核小体与 DNA 的束缚更加紧密，或者染色质结构更加紧凑，因为这种效应在用 α-二氟甲基鸟氨酸 (DFMO)（ODC 酶活性的特异性抑制剂）处理后是可逆的。北石染色质蛋白 HP-1beta 和核磷蛋白的释放受到阻碍，但核纤层蛋白 B、HDAC-1、HMGB、HMGN2 或 HMGA1 的释放不受阻碍，表明多胺对特定染色质蛋白复合物发挥选择性作用。此外，ODC 小鼠核小体的整体乙酰化以及特定甲基化不受影响，这意味着历史修饰酶的访问通常不受限制。多胺水平升高造成的异常染色质环境可能是上皮肿瘤生长和维持的必要先决条件。 (C) 2003 Elsevier Inc. 保留所有权利。
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 histories 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 northistone 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 historic 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. (C) 2003 Elsevier Inc. All rights reserved.