Single cell chromatin profiling to study epigenetic alterations of ovarian tumors

单细胞染色质分析研究卵巢肿瘤的表观遗传改变

• 批准号: 10506998
• 负责人: Sneha Gopalan
• 金额: $ 12.47万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10506998
• 关键词: Affect; Architecture; Bioinformatics; Cancer Model; Catalysis; Catalytic Domain; Cell Differentiation process; Cell Line; Cell Maintenance; Cells; Chromatin; Complex; Development; Differentiated Gene; Drug Targeting; EZH2 gene; Enzymes; Epigenetic Process; Exhibits; Focus Groups; Frequencies; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Genome; Goals; Heterogeneity; Histones; Impairment; Individual; Knock-out; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Measures; Methods; Mutation; Neoplasm Metastasis; Nucleic Acid Regulatory Sequences; Ovarian; Pathway interactions; Phase; Polycomb; Population; Process; Regulator Genes; Role; Running; Technology; Testing; Therapeutic; Time; Training; Tumor Biology; cancer cell; cancer stem cell; cancer therapy; cancer type; cell type; combinatorial; epigenetic regulation; epigenome; epigenomics; histone methyltransferase; human model; inhibitor; insight; knock-down; neoplastic cell; novel therapeutic intervention; novel therapeutics; ovarian neoplasm; overexpression; patient derived xenograft model; self-renewal; single-cell RNA sequencing; stem cell population; stem cell self renewal; targeted treatment; transcriptome; treatment effect; tumor; tumor growth; tumor heterogeneity; tumor progression; tumorigenesis

PROJECT SUMMARY An understanding of how epigenetic changes rewire the regulatory network of cancer cells would facilitate the development of new therapeutic strategies. However, tumor heterogeneity hinders the study of epigenetic landscapes in cancer. I propose to leverage a new single-cell genome profiling technology I recently developed to map epigenetic changes in single cells, allowing me to characterize different cell populations within ovarian tumors, including cancer stem cells (CSCs) and more differentiated cell types. These studies will uncover how the epigenome is re-wired upon inhibition of epigenetic enzymes implicated in multiple cancers. EZH2 is a histone methyltransferase that is often overexpressed in different types of cancer, including ovarian cancer, and inhibition of EZH2 has been shown to strongly reduce the aggressiveness of tumors by impairing metastasis, reducing invasiveness, and promoting differentiation. Yet, how EZH2 overexpression alters the repressive histone mark, H3K27me3 in each tumor cell type remains unknown. I propose three Aims, the first of which will use a combination of single cell Multi-CUT&Tag—a single cell profiling technology I recently developed—and scRNA-seq to characterize the epigenomic landscapes in each ovarian cancer cell type. In Aim 2, I will examine how perturbation of EZH2 alters the epigenetic architecture of tumor sub-populations, including CSCs, and identify how EZH2 promotes CSC self-renewal and tumor progression. Finally, in Aim 3, I will uncover the roles of genes and pathways subjected to epigenomic remodeling, in order to identify potential weaknesses that can be exploited therapeutically. Successful completion of these studies will provide considerable insight into the epigenetic regulation of CSCs in ovarian cancers and candidates for new therapies for ovarian cancer treatment. In addition, these studies will provide extensive training in tumor biology and single cell bioinformatics, which will be essential for my goal of running an independent group focused on tumor epigenetics.

项目总结 了解表观遗传变化如何重新连接癌细胞的调控网络将有助于 开发新的治疗策略。然而，肿瘤的异质性阻碍了表观遗传学的研究 巨蟹座的风景。我提议利用我最近开发的一项新的单细胞基因组图谱技术 绘制单个细胞的表观遗传学变化图，使我能够表征卵巢内不同的细胞群体 肿瘤，包括癌症干细胞(CSCs)和更多分化的细胞类型。这些研究将揭示 表观基因组是通过抑制与多种癌症有关的表观遗传酶而重新连接的。EZH2是一种 组蛋白甲基转移酶通常在不同类型的癌症中过度表达，包括卵巢癌， 而抑制EZH2已被证明通过损害 转移，减少侵袭，促进分化。然而，EZH2的过度表达如何改变 抑制性组蛋白标记、H3K27me3在每种肿瘤细胞类型中的表达尚不清楚。我提出了三个目标，第一个目标 其中将使用单细胞多重切割和标记的组合-单细胞图谱技术我最近 已开发和scRNA-seq以表征每种卵巢癌细胞类型的表观基因组图谱。在……里面 目的2，我将研究EZH2的扰动如何改变肿瘤亚群的表观遗传结构， 包括CSCs，并确定EZH2如何促进CSC自我更新和肿瘤进展。最后，在目标3中，我 将揭示受表观基因组重塑的基因和途径的作用，以确定潜在的 可以在治疗上加以利用的弱点。成功完成这些研究将提供 对卵巢癌中CSCs的表观遗传调控的相当深入的洞察和新的候选 卵巢癌的治疗方法。此外，这些研究将在肿瘤方面提供广泛的培训。 生物学和单细胞生物信息学，这对我管理一个独立小组的目标是必不可少的 专注于肿瘤表观遗传学。