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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要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然而，肿瘤异质性阻碍了表观遗传学的研究。我建议利用我最近开发的一种新的单细胞基因组分析技术。绘制单细胞的表观遗传变化图，使我能够表征卵巢内不同的细胞群肿瘤，包括癌症干细胞（CSC）和更多分化的细胞类型，这些研究将揭示其中的机制。 EZH2 与多种癌症相关的表观遗传酶受到抑制后，表观基因组会重新连接。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，抑制 EZH2 已被证明可以通过削弱肿瘤的活性来强烈降低肿瘤的侵袭性然而，EZH2 过度表达如何改变转移、减少侵袭性和促进分化。每种肿瘤细胞类型中的抑制性组蛋白标记 H3K27me3 仍然未知，我提出三个目标，第一个。其中将使用单细胞Multi-CUT&Tag的组合——我最近的一项单细胞分析技术开发了 scRNA-seq 来表征每种卵巢癌细胞类型的表观基因组景观。目标 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 CSC，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。将揭示经历表观基因组重塑的基因和通路的作用，以确定潜在的成功完成这些研究将提供可以在治疗上利用的弱点。对卵巢癌中 CSC 的表观遗传调控以及新的候选药物的候选者有深入的了解此外，这些研究将为肿瘤治疗提供广泛的培训。生物学和单细胞生物信息学，这对于我管理一个独立小组的目标至关重要专注于肿瘤表观遗传学。