随着二代测序技术的发展，海量基因组数据的获取越来越容易，如何从中提取合适特征、识别差异信号是研究的难点。染色质开放性是一种重要的表观基因组性质，蕴含着转录因子结合与核小体排布两个维度的信息。染色质开放性的差异信号是转录因子、核小体竞争性结合基因组的结果，本文通过染色质开放性的差异信号识别，发现了细胞衰老的转录因子结合、核小体排布改变，并将染色质开放性应用到了癌症溯源检测中，主要贡献分为如下两部分：（1）利用ATAC-seq识别了细胞衰老中的染色质开放性改变及其关键调控因子。首先，基于5种衰老相关状态的ATAC-seq数据，绘制细胞衰老的染色质开放性图谱，筛选细胞衰老中特异性开放的调控元件，发现了细胞衰老后异染色质区域异常活跃。然后，通过整合细胞衰老的基因表达数据、转录因子的motif和ChIP-seq信息，识别了bZIP家族的转录因子为细胞衰老的关键调控因子，并通过计算与实验结合的方式，验证了bZIP家族中的FOS转录因子对衰老相关分泌表型的调控作用。最后，通过核小体排布的分析，发现细胞衰老后180 bp以上的单核小体片段显著减少，与文献报道的衰老细胞核小体减少的结论相符。（2）开发了一种利用cfDNA片段化模式溯源癌症的分析方法。cfDNA由全身各组织细胞的基因组片段化产生，其片段化模式蕴含癌症的核小体排布信息。利用核小体周期与基因表达的负相关关系，参考健康组织细胞、各种癌症的基因表达数据，推断血浆游离DNA的组织来源分布，从而溯源癌症发生部位。本文提出了频谱加权核小体周期特征，能充分利用核小体周期信息，与基因表达的相关性较强，在测序深度足够的情况下能准确地溯源多种癌症。此外，该检测方法的预测效果会随着测序深度的增加而提升，在未来高深度测序的cfDNA中应用潜力巨大。总之，本文以转录因子、核小体调控下的染色质开放性为研究对象，通过差异信号识别与分析，筛选了细胞衰老的关键调控因子，提出了一种分类多种癌症病人的溯源检测方法。

With the development of next generation sequencing, it is easier to acquire whole genome sequencing data. However, the bottleneck of many studies is how to extract proper features and identify differential signals from the big data. Chromatin openness is an important epigenetic feature, which contains TFs binding and nucleosome positioning information. Differential Signals on chromatin openness are consequences of competitive genomic binding with TFs and nucleosome. Here, we use differential signal identification to recognize changes of TFs binding and nucleosome positioning during cellular senescence. Then we apply chromatin openness of cancer detection. My contribution can be divided into the following two parts.（1） Identify chromatin openness changes and its key regulator during cellular senescence using ATAC-seq. First, we produced ATAC-seq data of five senescence associated cell states to draw the chromatin openness maps of cellular senescence, screen regulatory element which is specifically open in cellular senescence and find that heterochromatin is activated after senescence. Second, we identify bZIP family as the key regulatory during senescence by integrating transcriptome, TF motif and ChIP-seq information. Then we validated FOS, one of bZIP family, regulates SASP with computation and experiment methods. Third, nucleosome positioning analysis found that ATAC-seq mono-nucleosome fragments longer than 180 bp is significantly reduced after senescence. This phenomenon supports previous senescence studies in which the number of nucleosomes decreased.（2） Develop an analytical method to infer cancer locations by cfDNA fragmentation pattern. Cell-free DNA is naturally fragmented from the genomes of many tissues and cells. Its fragmentation pattern contains nucleosome positioning information. By utilizing the negative correlation between nucleosome period and gene expression and integrating transcriptomes of healthy tissues and cancers, we can infer cfDNA tissue-of-origin and detect cancer. This paper developed spectral weighted period as a nucleosome feature. SWP can take full advantage of nucleosome period information and correlate well with gene expression. Our method can trace multiple cancers precisely as long as cfDNA sequencing coverage is enough. Moreover, the accuracy of this detection method will rise with the increase of coverage, which implies a huge potential of this method in the future.In a word, this paper studied the chromatin openness regulated by transcription factors and nucleosomes, discovered the key regulator of cellular senescence and developed a detection method to classify many kinds of cancer patients through differential signal identification.