Chromatin States Accurately Classify Cell Differentiation Stages

Gene expression is controlled by the concerted interactions between transcription factors and chromatin regulators. While recent studies have identified global chromatin state changes across cell-types, it remains unclear to what extent these changes are co-regulated during cell-differentiation. Here we present a comprehensive computational analysis by assembling a large dataset containing genome-wide occupancy information of 5 histone modifications in 27 human cell lines (including 24 normal and 3 cancer cell lines) obtained from the public domain, followed by independent analysis at three different representations. We classified the differentiation stage of a cell-type based on its genome-wide pattern of chromatin states, and found that our method was able to identify normal cell lines with nearly 100% accuracy. We then applied our model to classify the cancer cell lines and found that each can be unequivocally classified as differentiated cells. The differences can be in part explained by the differential activities of three regulatory modules associated with embryonic stem cells. We also found that the “hotspot” genes, whose chromatin states change dynamically in accordance to the differentiation stage, are not randomly distributed across the genome but tend to be embedded in multi-gene chromatin domains, and that specialized gene clusters tend to be embedded in stably occupied domains.基因表达由转录因子（transcription factors）与染色质调控因子（chromatin regulators）之间的协同互作所调控。尽管近期研究已鉴定出不同细胞类型间的全局染色质状态变化，但目前仍不清楚这些变化在细胞分化过程中被共同调控的程度。本研究整合公共领域获取的大型数据集，开展全面的计算分析：该数据集涵盖27种人类细胞系（含24种正常细胞系与3种癌细胞系）中5种组蛋白修饰（histone modifications）的全基因组结合位点（genome-wide occupancy）信息；随后从三种不同表征维度开展独立分析。我们基于细胞类型的全基因组染色质状态模式，对其分化阶段进行分类，发现该方法可实现近100%准确率的正常细胞系鉴定。随后我们将模型应用于癌细胞系分类，发现所有癌细胞系均可被明确归类为分化细胞。这类差异可部分通过与胚胎干细胞（embryonic stem cells）相关的三类调控模块的差异活性予以解释。我们还发现，染色质状态随分化阶段动态变化的“热点基因（hotspot genes）”并非随机分布于基因组中，而是倾向于嵌入多基因染色质结构域（multi-gene chromatin domains）内；同时特化基因簇（specialized gene clusters）往往位于稳定结合结构域（stably occupied domains）中。