Enhancer-promoter interactions are reconfigured through the formation of long-range multiway chromatin hubs as mouse ES cells exit pluripotency
Enhancer-promoter interactions are reconfigured through the formation of long-range multiway chromatin hubs as mouse ES cells exit pluripotency
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DOI：
10.1101/2023.02.08.527615
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发表时间：
2023-02
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通讯作者：
D. Lando;X. Ma;Y. Cao;A. Jartseva;T. Stevens;W. Boucher;N. Reynolds;B. Montibus;D. Hall;A. Lackner;R. Ragheb;M. Leeb;B. Hendrich;E. Laue
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作者：
D. Lando;X. Ma;Y. Cao;A. Jartseva;T. Stevens;W. Boucher;N. Reynolds;B. Montibus;D. Hall;A. Lackner;R. Ragheb;M. Leeb;B. Hendrich;E. Laue
增强子是结合转录因子、染色质调节因子和非编码转录物以调节靶基因表达的基因组DNA序列。已经发现它们从相对于基因的不同位置起作用，并且调节高达101 Mb的启动子的活性。在这里，我们报告了单个小鼠ES细胞的第一个3D基因组结构，因为它们被诱导退出多能性，通过形成阶段过渡并经历神经外胚层分化。为了直接研究增强子和启动子之间的相互作用如何在全基因组范围内重新配置，我们使用单细胞Hi-C确定了单倍体细胞的3D结构，其中我们可以明确地将接触映射到特定染色体。我们发现，有一个显着的重组的三维基因组结构，其中染色体间的混合在形成状态显着增加。这种混合与大量多路枢纽的形成有关，所述多路枢纽将具有相似染色质状态的增强子和启动子从通常彼此相隔许多Mb的通常5-8个远距离染色体位点聚集在一起。当细胞进入形成状态时，对多能性重要的基因退出与多路染色质枢纽内出现的增强子建立接触，这与这些结构变化在建立新的细胞身份中发挥重要作用一致。此外，我们发现不同的多路染色质枢纽，从而不同的增强子-启动子相互作用，在不同的个体细胞中形成。我们的研究结果表明，研究单细胞中的基因组结构对于确定细胞发生发育转变时增强子-启动子相互作用的关键变化非常重要。
Enhancers are genomic DNA sequences that bind transcription factors, chromatin regulators and non-coding transcripts to modulate the expression of target genes. They have been found to act from different locations relative to a gene and to modulate the activity of promoters up to ∼1 Mb away. Here we report the first 3D genome structures of single mouse ES cells as they are induced to exit pluripotency, transition through a formative stage and undergo neuroectodermal differentiation. In order to directly study how interactions between enhancers and promoters are reconfigured genome wide we have determined 3D structures of haploid cells using single cell Hi-C, where we can unambiguously map the contacts to particular chromosomes. We find that there is a remarkable reorganisation of 3D genome structure where inter-chromosomal intermingling increases dramatically in the formative state. This intermingling is associated with the formation of a large number of multiway hubs that bring together enhancers and promoters with similar chromatin states from typically 5-8 distant chromosomal sites that are often separated by many Mb from each other. Genes important for pluripotency exit establish contacts with emerging enhancers within multiway chromatin hubs as cells enter the formative state, consistent with these structural changes playing an important role in establishing new cell identities. Furthermore, we find that different multiway chromatin hubs, and thus different enhancer-promoter interactions, are formed in different individual cells. Our results suggest that studying genome structure in single cells will be important to identify key changes in enhancer-promoter interactions that occur as cells undergo developmental transitions.