Katelyn R Titus, Zoltan Simandi, Harshini Chandrashekar, Dominik Paquet, Jennifer E Phillips-Cremins
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引用次数: 0
摘要
DNA 折叠成高阶结构,形成基因组功能,并由基因组功能所形成。在细胞命运转换过程中,长程环路在建立新基因表达模式中的作用仍鲜为人知。在此,我们研究了在神经谱系承诺过程中细胞特异性环路与 RNA 聚合酶 II(RNA Pol II)之间的联系。我们发现,在人类诱导多能干细胞(hiPSC)分化为神经祖细胞(NPC)和有丝分裂后神经元的过程中,有数千个环路退役或新生。在hiPSC向NPC和NPC向神经元转变的过程中,从RNA Pol II起始转为伸长的基因锚定细胞特异性环路的可能性是被抑制基因的4倍以上。当伸长基因连接在细胞特异性启动子-增强子环路中,而不是不变的启动子-增强子环路或启动子-启动子环路中,或未连接时,会表现出显著的 mRNA 上调。从抑制状态过渡到 RNA Pol II 启动状态的基因表现出轻微的 mRNA 增加,与环路状态无关。我们的数据将神经细胞命运转变过程中细胞特异性环路和 RNA Pol II 介导的强健伸长联系起来。
Cell-type-specific loops linked to RNA polymerase II elongation in human neural differentiation.
DNA is folded into higher-order structures that shape and are shaped by genome function. The role of long-range loops in the establishment of new gene expression patterns during cell fate transitions remains poorly understood. Here, we investigate the link between cell-specific loops and RNA polymerase II (RNA Pol II) during neural lineage commitment. We find thousands of loops decommissioned or gained de novo upon differentiation of human induced pluripotent stem cells (hiPSCs) to neural progenitor cells (NPCs) and post-mitotic neurons. During hiPSC-to-NPC and NPC-to-neuron transitions, genes changing from RNA Pol II initiation to elongation are >4-fold more likely to anchor cell-specific loops than repressed genes. Elongated genes exhibit significant mRNA upregulation when connected in cell-specific promoter-enhancer loops but not invariant promoter-enhancer loops or promoter-promoter loops or when unlooped. Genes transitioning from repression to RNA Pol II initiation exhibit a slight mRNA increase independent of loop status. Our data link cell-specific loops and robust RNA Pol II-mediated elongation during neural cell fate transitions.