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Regulation of interferon signaling in melanoma by the cohesin complex protein STAG2 via 3D genome organization

粘连蛋白复合物 STAG2 通过 3D 基因组组织调节黑色素瘤中的干扰素信号传导

基本信息

批准号：
10905899
负责人：
Bin Zheng
金额：
$ 37.44万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10905899
关键词：
3-Dimensional Address BRAF gene Binding Binding Sites Biology CD8-Positive T-Lymphocytes CSPG6 gene Cancer Biology Cell Nucleus ChIP-seq Chromatin Chromatin Loop Chromatin Structure Clustered Regularly Interspaced Short Palindromic Repeats Compensation Complex Enhancers Future Gene Expression Gene Expression Regulation Genetic Transcription Genome Hi-C Human Human Genome ISGF3G protein Immune Evasion In Vitro Interferon Type I Interferons Length Malignant Neoplasms Mediating Melanoma Cell Modeling Molecular Mus Mutate Mutation Pathway interactions Regulation Resistance Role Sampling Signal Pathway Signal Transduction Solid Neoplasm T cell infiltration T-Lymphocyte Testing Translational Research Tumor Immunity Tumor Suppressor Proteins anti-PD-1 anti-PD1 therapy biomarker discovery cancer cell cohesin exhaustion immune checkpoint blockade insight knock-down malignant phenotype mammalian genome melanoma mutant novel paralogous gene programmed cell death ligand 1 promoter protein complex response small hairpin RNA targeted treatment transcription factor transcriptome sequencing tumor

项目摘要

Summary Mammalian genomes is folded within the nucleus in a highly organized fashion. The cohesin complex participates in the organization of 3D genome through generating and maintaining DNA loops. The tumor suppressor STAG2, which encodes a core subunit of the cohesin complex, is frequently mutated in various cancers. However, the impact of STAG2 inactivation on 3D genome organization in cancer cells, especially the long-range enhancer-promoter contacts and subsequent gene expression control, remains poorly understood. In our preliminary studies, we have carried out RNA-seq, ChIP-seq as well as Hi-C analyses in melanoma cells stably expressing inducible shRNA of STAG2. We have shown that depletion of STAG2 in melanoma cells leads to expansion of topologically associated domains (TADs) at sites where binding of STAG2 is switched to its paralog STAG1. We also identified Interferon Regulatory Factor 9 (IRF9) as a putative direct target of STAG2 in melanoma cells and demonstrated that loss of STAG2 activates IRF9 to enhance type I interferon signaling and increases the expression of PD-L1. Based on these preliminary findings, we hypothesize that loss of STAG2 results in dysregulation of type I interferon signaling in melanoma via perturbation of 3D genome organization. In aim 1, we will characterize the molecular mechanism underlying the regulation of type I interferon response by STAG2 in melanoma via modulating 3D genome organization. We will also examine the chromatin interactions at the IRF9 locus and other targets in STAG2 wildtype and STAG2 mutant human melanoma samples. In aim 2, we will systematically characterize STAG2-specific chromatin loops and investigate the effects of STAG2 inactivation on the enhancer-promoter interactome in melanoma cells by carrying out STAG2- and H3K27ac- HiChIP analyses. In aim 3, we will examine the roles of STAG2 in regulating tumor-induced immune evasion and in determining the sensitivity to anti-PD-1 immune checkpoint blockade in melanoma. Findings from the proposed study will very likely reveal functions of STAG2 within the cohesin complex that contribute to the malignant phenotypes in STAG2 mutant cancer arising from 3D genome perturbation.

总结