T细胞淋巴瘤的表观遗传调控

Gene regulation is a complex system of genetic and epigenetic modification. The study of the epigenome of a disease has a very important scientific significance for in-depth understanding of pathogenesis and optimal diagnosis and treatment. This project will study the human cutaneous T cell lymphoma (CTCL) as the research object and develop new technologies like ATAC-seq for rapid detection of DNA open chromatin sites from micro-amount of T lymphocytes from normal and patients in vivo. The project will develop single cell sequencing and bioinformatics technologies to integrative analyze various types of genomic data, reveal the epigenetic signature of CTCL, and to construct CTCL tumor-specific, patient-specific and cell-specific gene regulatory networks. The project will also study the mechanism of the epigenome and critical transcription factors regulating the patients’ drug sensitivity by tracking the epigenomic profiling of the patients at various time points during the treatment of histone deacetylase inhibitor anticancer drugs. The project will establish predictive model and provide a scientific basis for patients’ precision medicine. This project will be the first real-time construction of the personalized epigenetic regulatory networks of cancer, and will establish a template for the study of the personalized epigenetic regulation mechanism of other diseases, which is of great scientific significance to promote the development of precision medicine.

基因调控是一个遗传和表观遗传修饰共同作用的复杂系统。对疾病的表观遗传基因组的研究对于深入了解致病机理、优化诊断和治疗方案都具有非常重要的科学意义。本项目将以人类T细胞淋巴瘤（CTCL）为研究对象，发展ATAC-seq新技术快速检测正常人和患者微量活体T淋巴细胞中染色质开放位点。项目将开发单细胞测序和生物信息技术，整合分析各类组学数据，解析CTCL表观遗传指纹，构建CTCL肿瘤特异性、患者特异性和细胞特异性基因调控网络。项目还将通过追踪患者在组蛋白脱乙酰酶抑制剂抗癌药物治疗过程中各个时间点的表观遗传状态，在时间尺度上深入研究表观遗传基因组和关键性转录因子对患者药物敏感性的动态调控机制，建立预测模型，并为患者的精准医疗方案提供科学依据。本项目将是首个实时构建癌症个性化表观遗传调控网络的工作，并将为研究其他疾病的个性化表观遗传调控机制建立模板，对推动精准医疗的发展有非常重要的科学意义。

基因调控是一个遗传和表观遗传修饰共同作用的复杂系统。对疾病的表观遗传基因组的研究对于深入了解致病机理、优化诊断和治疗方案都具有非常重要的科学意义。我们以CTCL、新冠疾病、系统性硬化症(SSc)、类风湿性关节炎(RA)、肥胖、复发性流产疾病、T细胞发育体系、NK细胞发育体系、视网膜细胞发育体系等病理或生理发育过程为研究对象，利用ATAC-seq和单细胞测序技术，开发单细胞ATAC-seq(ftATAC-seq)新技术快速检测微量活体细胞中基因表达和染色质开放位点。我们还开发了ATAC-seq技术的分析流程工具(ATAC-pipe和APEC)，单细胞测序数据稀疏表达矩阵恢复算法(WEDGE)，解析疾病状态和细胞发育过程表观遗传指纹和基因表达特征，构建转录因子调控网络。我们的研究应用多种组学技术和开发相应生物信息学算法构建疾病衍生和细胞发育过程中的表观遗传调控网络，为研究其他疾病的个性化表观遗传调控机制建立模板，对推动精准医疗的发展有非常重要的科学意义。