Single-cell chromatin profiles reveal a spectrum of stem cell epigenetic states

Chromatin profiling provides a versatile means to chart gene regulatory elements and investigate their mechanisms of regulation. However, current methods yield ensemble profiles that are insensitive to cell-to-cell variation. This is a major limitation as transcriptional states and phenotypes vary markedly across individual cells. Here we combined microfluidics, DNA barcoding and sequencing to profile chromatin at single-cell resolution. We demonstrate the technology by profiling a mixture of ES cells, fibroblasts and hematopoietic progenitors, and deconvoluting in silico high-quality maps for each cell type. We find that regulatory elements differ in their variability, with bivalent promoters showing particularly heterogeneous patterns across single-cells that in contrast with to the relative stability of active promoters and enhancers. Finally, we document a spectrum of ES cell states whose chromatin landscapes exhibit varying degrees of pluripotency and priming signatures. Our study presents an innovative single-cell analysis tool for single-cell analysis, and reveals aspects of epigenetic heterogeneity not be captured by transcriptional analysis alone.

染色质图谱分析（Chromatin profiling）是绘制基因调控元件、探究其调控机制的通用手段。然而现有方法仅能生成整体水平的染色质图谱，无法捕捉细胞间的异质性。鉴于单个细胞的转录状态与表型存在显著差异，这一局限成为当前研究的主要瓶颈。本研究结合微流控技术、DNA条形码与测序手段，实现了单细胞分辨率下的染色质图谱分析。我们通过对胚胎干细胞（ES cells）、成纤维细胞与造血祖细胞的混合样本进行染色质图谱分析，并通过计算机模拟解析出每种细胞类型的高质量染色质图谱，以此验证了该技术的可行性。研究发现不同调控元件的异质性存在显著差异：二价启动子（bivalent promoters）在单个细胞间呈现出高度异质的染色质模式，而活跃启动子与增强子则相对稳定，二者形成鲜明对比。最后，我们观测到一系列胚胎干细胞状态，其染色质景观呈现出不同程度的多能性与预激活特征。本研究开发了一款创新的单细胞分析工具，并揭示了仅通过转录分析无法捕捉到的表观遗传异质性特征。