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.