Functions of KAT2A and KAT2B in intestinal homeostasis and colon cancer.

KAT2A 和 KAT2B 在肠道稳态和结肠癌中的功能。

• 批准号: 10457965
• 负责人: MAI UYEN NGUYEN
• 金额: $ 4.27万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457965
• 关键词: Acetyltransferase; American Cancer Society; ApcMin/+ mice; Attention; Binding Sites; Biological Assay; Cancer Etiology; Cancerous; Candidate Disease Gene; Cell Differentiation process; Cell Proliferation; Cells; Cessation of life; ChIP-seq; Chromatin; Clinical; Colon; Colon Carcinoma; Colorectal Cancer; Communication; DNA Sequence Alteration; Data; Death Rate; Differentiated Gene; Drug Targeting; Enzymes; Epigenetic Process; Epithelial; Gene Expression; Gene Targeting; Genes; Genetic; Heterogeneity; Histology; Histone Acetylation; Histones; Histopathology; Homeostasis; Incidence; Intestines; Knock-out; Knowledge; Lead; Lysine; Malignant Neoplasms; Mass Spectrum Analysis; Modeling; Mus; Oncogenes; Ontology; Organoids; Outcome; Phenotype; Post-Translational Protein Processing; Proliferating; Quantitative Reverse Transcriptase PCR; Research Personnel; Role; Suppressor-Effector T-Lymphocytes; Testing; Tissue-Specific Gene Expression; Tissues; Training; Transcript; Tumor Suppressor Proteins; United States; Universities; Woman; Work; base; cancer type; collaborative environment; colon cancer progression; colon cancer treatment; colon tumorigenesis; differential expression; epigenome; epigenomics; gene function; histone acetyltransferase; histone modification; improved; in vivo evaluation; intestinal epithelium; intestinal homeostasis; men; mouse model; novel; novel drug class; progenitor; screening; skills; statistics; stem; stem cell proliferation; targeted cancer therapy; targeted treatment; therapeutic target; transcriptome; transcriptome sequencing; tumor; tumor heterogeneity; tumorigenesis

Project Summary/Abstract The genetics behind colon cancer is now well described, but even among tumors with identical genetic mutations, tumor heterogeneity remains problematic in the clinical setting. Epigenomics, including histone post- translational modifications (PTMs), can modulate gene expression and explain heterogeneity. Epigenomic regulators have gained attention as candidates for targeted cancer therapy. However, there are still large gaps in understanding the role of epigenomics in colon cancer. This proposal’s primary objective is to uncover the roles of KAT2A and KAT2B in normal intestinal epithelium homeostasis and colon cancer. These genes encode histone lysine acetyltransferase enzymes, whose functions have not yet been elucidated in colon cancer. KAT2A is normally expressed in intestinal stem and proliferative cells, while KAT2B is enriched in differentiated epithelium. In tumors, KAT2A levels are elevated, while KAT2B levels are reduced. I hypothesize that KAT2A catalyzes histone PTMs to promote proliferative gene expression and drive colon tumorigenesis, while KAT2B promotes differentiation gene expression and suppresses colon tumorigenesis. Alternatively, these lysine acetyltransferases could function redundantly. The rationale for this study is based on preliminary data showing that KAT2A and KAT2B are differentially expressed in normal versus cancerous colon tissue and the observation that they can catalyze histone acetyl as well as non-acetyl histone modifications. Importantly, these factors have not been functionally tested in vivo in the intestine. Aim 1 will use novel genetic mouse models to assess the effects of KAT2A/KAT2B knockout on intestinal homeostasis and colon cancer by employing histology studies, organoid assays, tumor quantification, and qRT-PCR screening. Aim 2 will use histone PTM mass spectrometry analysis, RNA-seq, and ChIP-seq to determine 1) important acetyl and non-acetyl histone PTMs catalyzed by KAT2A/KAT2B and 2) how the binding sites of KAT2A/KAT2B and their PTMs correlate with changes in the transcriptome. The significance of this proposal is that it will improve our understanding of epigenetic mechanisms in colon cancer and introduces two candidate genes, KAT2A and KAT2B, to target in colon cancer. With the training plan devised by Dr. Michael Verzi, the applying fellow will 1) gain expertise in genetics and cancer, 2) develop effective scientific communication skills, and 3) prepare to lead a lab as an independent translational cancer researcher within a nurturing, resourceful, and collaborative environment at Rutgers University.

项目摘要/摘要 现已很好地描述了结肠癌背后的遗传学，但即使在具有相同遗传的肿瘤中 突变，肿瘤异质性在临床环境中仍然有问题。表观基因组学，包括Hisstone Post- 翻译修饰（PTM）可以调节基因表达并解释异质性。表观基因组 监管机构已成为靶向癌症治疗的候选者。但是，仍然很大 了解表观基因组学在结肠癌中的作用的差距。 该提议的主要目标是揭示Kat2a和Kat2b在正常肠上皮的角色 稳态和结肠癌。这些基因编码组蛋白赖氨酸乙酰转移酶，谁 在结肠癌中尚未阐明功能。 Kat2a通常在肠干和 增殖细胞，而Kat2b富含分化的上皮。在肿瘤中，Kat2a水平升高， 而KAT2B水平降低。我假设KAT2A催化组蛋白PTMs以促进增殖 基因表达和驱动结肠肿瘤发生，而KAT2B促进了分化基因表达和 抑制结肠肿瘤发生。或者，这些赖氨酸乙酰转移酶可以冗余地发挥作用。这 这项研究的基本原理基于初步数据，表明Kat2a和Kat2b是差异的 在正常的与取消结肠组织中表达，观察到它们可以催化组蛋白乙酰基 以及非乙酰基希斯通的修改。重要的是，这些因素尚未在体内进行功能测试 在肠道中。 AIM 1将使用新型的遗传小鼠模型来评估KAT2A/KAT2B敲除的影响 通过采用组织学研究，器官测定，肿瘤，肠内稳态和结肠癌 定量和QRT-PCR筛选。 AIM 2将使用组蛋白PTM质谱分析RNA-Seq， 和chip-seq确定1）由kat2a/kat2b和 2）KAT2A/KAT2B及其PTMS的结合位点与转录组的变化相关。 该提议的意义在于，它将提高我们对表观遗传机制的理解 癌症并引入两个候选基因Kat2a和Kat2b，以靶向结肠癌。在培训中 迈克尔·韦尔西（Michael Verzi）博士设计的计划，适用研究员1）在遗传学和癌症方面获得专业知识，2）发展 有效的科学沟通技巧和3）准备领导实验室作为独立翻译癌 罗格斯大学的培养，足智多谋和协作环境中的研究人员。