Department of Internal Medicine III, University Hospital Regensburg, 93053, Regensburg, Germany.
Sandoz GmbH, Biochemiestraße 10, 6336, Langkampfen, Austria.
Nat Commun. 2022 Jul 25;13(1):4301. doi: 10.1038/s41467-022-31892-2.
Cohesin is a major structural component of mammalian genomes and is required to maintain loop structures. While acute depletion in short-term culture models suggests a limited importance of cohesin for steady-state transcriptional circuits, long-term studies are hampered by essential functions of cohesin during replication. Here, we study genome architecture in a postmitotic differentiation setting, the differentiation of human blood monocytes (MO). We profile and compare epigenetic, transcriptome and 3D conformation landscapes during MO differentiation (either into dendritic cells or macrophages) across the genome and detect numerous architectural changes, ranging from higher level compartments down to chromatin loops. Changes in loop structures correlate with cohesin-binding, as well as epigenetic and transcriptional changes during differentiation. Functional studies show that the siRNA-mediated depletion of cohesin (and to a lesser extent also CTCF) markedly disturbs loop structures and dysregulates genes and enhancers that are primarily regulated during normal MO differentiation. In addition, gene activation programs in cohesin-depleted MO-derived macrophages are disturbed. Our findings implicate an essential function of cohesin in controlling long-term, differentiation- and activation-associated gene expression programs.
黏合蛋白是哺乳动物基因组的主要结构成分，对于维持环结构至关重要。虽然在短期培养模型中急性消耗黏合蛋白提示其对稳态转录回路的重要性有限，但长期研究受到复制过程中黏合蛋白必需功能的阻碍。在这里，我们在有丝分裂后分化环境中研究基因组结构，即人类血液单核细胞（MO）的分化。我们在整个基因组中对 MO 分化（分化为树突状细胞或巨噬细胞）过程中的表观遗传、转录组和 3D 构象景观进行了分析和比较，并检测到许多结构变化，从更高层次的隔室到染色质环。环结构的变化与黏合蛋白结合以及分化过程中的表观遗传和转录变化相关。功能研究表明，siRNA 介导的黏合蛋白（以及在较小程度上还有 CTCF）耗竭会显著扰乱环结构，并扰乱主要在正常 MO 分化过程中受到调控的基因和增强子。此外，黏合蛋白耗尽的 MO 衍生巨噬细胞中的基因激活程序受到干扰。我们的研究结果表明，黏合蛋白在控制长期分化和激活相关基因表达程序方面具有重要功能。
