ABSTRACT Immunosuppressive drugs such as cyclosporin A (CsA) can elicit hepatotoxicity by affecting gene expression. Here, we address the link between CsA and large-scale chromatin organization in HepG2 hepatocarcinoma cells. We show the existence of lamina-associated domains (LADs) interacting with lamin A, lamin B, or both. These ‘A-B’, ‘A-only’ and ‘B-only’ LADs display distinct fates after CsA treatment: A-B LADs remain constitutive or lose A, A-only LADs mainly lose A or switch to B, and B-only LADs remain B-only or acquire A. LAD rearrangement is overall uncoupled from changes in gene expression. Three-dimensional (3D) genome modeling predicts changes in radial positioning of LADs as LADs switch identities, which are corroborated by fluorescence in situ hybridization. Our results reveal interplay between A- and B-type lamins on radial locus positioning, suggesting complementary contributions to large-scale genome architecture. The data also unveil a hitherto unsuspected impact of cytotoxic drugs on genome conformation.Abbreviations: ChIP-seq: chromatin immunoprecipitation sequencing; CsA: cyclosporin A; FISH; fluorescence in situ hybridization; ICMT: isoprenylcysteine methyltransferase; LAD: lamina-associated domain; TAD: topologically-associated domain

中文翻译：

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lamin A 和 lamin B LAD 对染色质径向定位的相互作用

摘要 免疫抑制药物如环孢菌素 A (CsA) 可通过影响基因表达引起肝毒性。在这里，我们解决了 CsA 与 HepG2 肝癌细胞中大规模染色质组织之间的联系。我们展示了与 lamin A、lamin B 或两者相互作用的 lamina 相关域 (LAD) 的存在。这些“A-B”、“仅 A”和“仅 B”LAD 在 CsA 处理后显示出不同的命运：AB LAD 保持组成型或失去 A，仅 A 的 LAD 主要失去 A 或转换为 B，仅 B法援署保持 B-only 或获得 A。法援署重排总体上与基因表达的变化无关。三维 (3D) 基因组建模预测 LAD 径向定位的变化，因为 LAD 切换身份，荧光原位杂交证实了这一点。我们的结果揭示了 A 型和 B 型核纤层蛋白在径向基因座定位上的相互作用，表明对大规模基因组结构的互补贡献。数据还揭示了细胞毒性药物对基因组构象的迄今为止未曾预料的影响。缩写：ChIP-seq：染色质免疫沉淀测序；CsA：环孢菌素A；鱼; 荧光原位杂交；ICMT：异戊二烯半胱氨酸甲基转移酶；LAD：叶片相关域；TAD：拓扑相关域 层相关域；TAD：拓扑相关域 层相关域；TAD：拓扑相关域