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

免疫抑制药物如环孢菌素A（CsA）可以通过影响基因表达来引起肝毒性。在这里，我们解决了HepG2肝癌细胞中CsA与大规模染色质组织之间的联系。我们显示了与层蛋白A，层蛋白B或两者相互作用的层状相关域（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保持本构或丢失A，仅A的LAD主要丢失A或转换为B，并且仅B LAD仅保留B或获得A。LAD重排与基因表达的变化总体无关。三维（3D）基因组建模可预测LAD切换身份时LAD径向位置的变化，这可通过原位荧光得到证实杂交。我们的研究结果揭示了A型和B型核纤层蛋白在径向位点定位上的相互作用，表明对大规模基因组结构的互补贡献。数据还揭示了迄今为止无毒的细胞毒性药物对基因组构象的影响。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：层关联域；TAD：拓扑相关的域