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The cis-regulatory dynamics of embryonic development at single-cell resolution

机译：单细胞分辨率下胚胎发育的顺式调控动力学。

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Understanding how gene regulatory networks control the progressive restriction of cell fates is a long-standing challenge. Recent advances in measuring gene expression in single cells are providing new insights into lineage commitment. However, the regulatory events underlying these changes remain unclear. Here we investigate the dynamics of chromatin regulatory landscapes during embryogenesis at single-cell resolution. Using single cell combinatorial indexing assay for transposase accessible chromatin with sequencing (sci-ATAC-seq)(1), we profiled chromatin accessibility in over 20,000 single nuclei from fixed Drosophila melanogaster embryos spanning three landmark embryonic stages: 2-4 h after egg laying (predominantly stage 5 blastoderm nuclei), when each embryo comprises around 6,000 multipotent cells; 6-8 h after egg laying (predominantly stage 10-11), to capture a midpoint in embryonic development when major lineages in the mesoderm and ectoderm are specified; and 10-12 h after egg laying (predominantly stage 13), when each of the embryo's more than 20,000 cells are undergoing terminal differentiation. Our results show that there is spatial heterogeneity in the accessibility of the regulatory genome before gastrulation, a feature that aligns with future cell fate, and that nuclei can be temporally ordered along developmental trajectories. During mid-embryogenesis, tissue granularity emerges such that individual cell types can be inferred by their chromatin accessibility while maintaining a signature of their germ layer of origin. Analysis of the data reveals overlapping usage of regulatory elements between cells of the endoderm and non-myogenic mesoderm, suggesting a common developmental program that is reminiscent of the mesendoderm lineage in other species(2-4). We identify 30,075 distal regulatory elements that exhibit tissue-specific accessibility. We validated the germ-layer specificity of a subset of these predicted enhancers in transgenic embryos, achieving an accuracy of 90%. Overall, our results demonstrate the power of shotgun single-cell profiling of embryos to resolve dynamic changes in the chromatin landscape during development, and to uncover the cis-regulatory programs of metazoan germ layers and cell types.
机译：长期以来，了解基因调控网络如何控制细胞命运的逐步限制是一个长期的挑战。测量单细胞基因表达的最新进展为谱系承诺提供了新的见识。但是，这些变化背后的监管事件仍然不清楚。在这里，我们研究了在单细胞分辨率的胚胎发生过程中染色质调控景观的动力学。使用单细胞组合索引测定法对转座酶可及的染色质进行测序（sci-ATAC-seq）（1），我们在跨越三个里程碑式胚胎阶段（产蛋后2-4小时）的果蝇固定果蝇的20,000个单核中分析了染色质可及性（主要是第5阶段的胚盘细胞核），此时每个胚胎包含约6,000个专能细胞；产卵后6-8小时（主要是10-11期），以便在指定中胚层和外胚层的主要谱系时捕获胚胎发育的中点；以及在产卵后10-12小时（主要是第13阶段），当胚胎的20,000多个细胞中的每个细胞都进行终末分化时。我们的研究结果表明，在胃小肠化之前，调节基因组的可及性存在空间异质性，这一特征与未来的细胞命运保持一致，并且细胞核可以沿发育轨迹在时间上有序。在胚胎中期发育过程中，会出现组织粒度，从而可以通过染色质的可及性来推断单个细胞类型，同时保持其原始生殖层的特征。数据分析显示内胚层和非肌源性中胚层细胞之间调节元件的重叠使用，这表明一个共同的发育程序让人想起其他物种的中胚层谱系（2-4）。我们确定了30,075个具有组织特异性可及性的远端调节元件。我们验证了这些预测的增强子在转基因胚胎中的子层特异性，实现了90％的准确性。总的来说，我们的结果证明了of弹枪的胚胎单细胞谱分析能够解决发育过程中染色质景观的动态变化，并揭示后生菌胚层和细胞类型的顺式调控程序。

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