Genomics Core

摘要-基因组学，表观基因组学和生物信息学核心 基因组学，表观基因组学和生物信息学核心将提供人员，设备和专业知识， 支持表观遗传疗法孢子的所有项目。核心将是设计和执行 基因组和表观基因组实验，数据采集，质量控制，生物信息学分析，数据 管理、共享和分配。它将与所有SPORE项目密切合作， 病理学/生物标本核心。项目1通过抑制细胞周期蛋白依赖性激酶研究免疫致敏作用 CDK9。它将发现临床靶向CDK是否也是表观遗传调节因子，并进行临床前研究。 以及使用CDK抑制剂，DNA，联合表观遗传疗法和免疫疗法的临床研究 甲基转移酶（DNMT）抑制剂和免疫检查点抑制剂。核心将分析（i）基因 在肿瘤和免疫细胞中的表达和染色质可及性 CDK 9抑制剂，（ii）CDK 4、6和7抑制对DNA甲基化和基因表达的全基因组效应 （iii）支持临床前研究和结合CDK 9、DNMT和免疫调节剂的临床试验。 通过分析收集的样品的转录组学和表观遗传学参数（基因 通过RNA-seq、DNA甲基化表达和表达内源性逆转录病毒和重复元件 通过RRBS）和免疫细胞参数（分选的T细胞中的基因表达和耗竭标志物）。的 核心还将进行全外显子组测序（WES），以确定基线DNA突变和DNA 甲基化谱预测应答。项目2关注DNMT抑制剂之间的表观遗传协同作用 和Polycomb抑制复合物亚基EZH 1/2用于治疗实体瘤。核心将分析和 整合DNA甲基化、ChIP-seq、RNA-seq和WES数据，以评估DNMT和 EZH 1/2抑制剂，并对肿瘤组织进行单细胞RNA-seq分析，以描述肿瘤相关的 免疫人群。项目3将低甲基化剂诱导炎性体信号传导与 聚ADP-核糖基化的抑制剂以诱导癌细胞死亡。核心将评估全基因组， LINE-1重复甲基化。将分析RNA-seq数据的ERV和其他重复序列的表达。 肿瘤中的元素和分类的免疫细胞。

Abstract - Genomics, Epigenomics and Bioinformatics Core The Genomics, Epigenomics, and Bioinformatics Core will provide personnel, equipment, and expertise to support all projects of the Epigenetic Therapy SPORE. The Core will be a resource for design and execution of genomic and epigenomic experiments, data acquisition, quality control, bioinformatic analysis, data management, sharing and distribution. It will closely cooperate with all SPORE Projects and the Pathology/Biospecimen Core. Project 1 studies immune-sensitization by inhibition of cyclin-dependent kinase CDK9. It will discover whether clinically targetable CDKs are also epigenetic regulators and conduct pre-clinical and clinical studies of combined epigenetic therapy and immunotherapy using CDK inhibitors, DNA methyltransferase (DNMT) inhibitors and immune checkpoint inhibitors. The Core will analyze (i) gene expression and chromatin accessibility in tumor and immune cells in preclinical models of tumors treated with CDK9 inhibitors, (ii) genome-wide effects of CDK4, 6 and 7 inhibition on DNA methylation and gene expression, and (iii) support preclinical studies and a clinical trial combining CDK9, DNMT and immune checkpoints inhibitors by the analysis of collected samples for transcriptomic and epigenetic parameters (gene expression and expression of endogenous retroviruses and repetitive elements by RNA-seq, DNA methylation by RRBS) and immune cell parameters (gene expression and markers of exhaustion in sorted T cells). The Core will also perform whole exome sequencing (WES) to determine whether baseline DNA mutation and DNA methylation profiles predict response. Project 2 is focused on epigenetic synergy between inhibitors of DNMT and Polycomb repressive complex subunits EZH1/2 for therapy in solid tumors. The Core will analyze and integrate DNA methylation, ChIP-seq, RNA-seq and WES data to assess the combinatory effects of DNMT and EZH1/2 inhibitors and perform single-cell RNA-seq analysis of the tumor tissue to delineate tumor-associated immune populations. Project 3 combines induction of inflammasome signaling by hypomethylating agents with inhibitors of polyADP-ribosylation to induce death of cancer cells. The Core will assess genome-wide and LINE-1 repeat methylation. RNA-seq data will be analyzed for expression of ERVs and other repetitive elements in tumors and sorted immune cells.