Despite huge advances in stem-cell, single-cell and epigenetic technologies, the precise molecular mechanisms that determine lineage specification remain largely unknown. Applying an integrative multiomics approach, e.g. combining single-cell RNA-seq, single-cell ATAC-seq together with cell-type-specific DNA methylation and 3D genome measurements, we systematically map the regulatory landscape in the mouse neocortex in vivo. Our analysis identifies thousands of novel enhancer-gene pairs associated with dynamic changes in chromatin accessibility and gene expression along the differentiation trajectory. Crucially, we provide evidence that epigenetic remodeling generally precedes transcriptional activation, yet true priming appears limited to a subset of lineage-determining enhancers. Notably, we reveal considerable heterogeneity in both contact strength and dynamics of the generally cell-type-specific enhancer-promoter contacts. Finally, our work suggests a so far unrecognized function of several key transcription factors which act as putative "molecular bridges" and facilitate the dynamic reorganization of the chromatin landscape accompanying lineage specification in the brain.

中文翻译：

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多元组学分析显示皮质发育过程中广泛的表观基因组重塑

尽管干细胞，单细胞和表观遗传学技术取得了巨大进步，但确定谱系规格的精确分子机制仍然未知。应用综合的多组学方法，例如将单细胞RNA-seq，单细胞ATAC-seq与细胞类型特异性DNA甲基化和3D基因组测量相结合，我们系统地绘制了小鼠新皮层体内的调节图谱。我们的分析鉴定了成千上万的新型增强子-基因对，它们与染色质可及性和基因表达沿分化轨迹的动态变化有关。至关重要的是，我们提供证据表明表观遗传重塑通常先于转录激活，但真正的启动作用似乎仅限于谱系确定增强子的子集。值得注意的是 我们揭示了一般细胞类型特异性增强子-启动子接触的接触强度和动力学都存在相当大的异质性。最后，我们的工作提出了迄今为止尚不清楚的几种关键转录因子的功能，这些转录因子充当推定的“分子桥”，并促进大脑中沿袭谱系规范的染色质景观的动态重组。