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CHD5 dosage in epigenetic control of Cancer, Infertility, and Autism

CHD5 剂量在癌症、不孕症和自闭症的表观遗传控制中的作用

基本信息

批准号：
8693343
负责人：
Alea A. Mills
金额：
$ 28.35万
依托单位：
COLD SPRING HARBOR LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8693343
关键词：
1p36 Affect Architecture Autistic Disorder Behavior Behavioral Binding Bioinformatics Biological Biological Assay Brain Cancer Control Cells ChIP-seq Chimera organism Chromatin Chromosomes Clinical Complement Copy Number Polymorphism DNA Damage Development Diagnostic Neoplasm Staging Diagnostic tests Disease Disease Outcome Disease Pathway Engineering Ensure Epigenetic Process Equilibrium Etiology Event Fertility Fibroblasts Foundations Fragile X Syndrome Future Gene Expression Gene Expression Profile Genetic Genome Genomics Germ Cells Goals Health Histones Homeostasis Human Incidence Infertility Intervention Male Infertility Malignant Neoplasms Maps Mediating Microscopy Modeling Molecular Profiling Mus Neurons Normal Cell Normal tissue morphology Nuclear Nuclear Structure Partner in relationship Pattern Phenotype Play Process Proteins RNA-Binding Proteins Reader Reading Reporting Role Sperm Maturation Spermatids Syndrome System Testing Therapeutic Tumor Suppressor Proteins Wild Type Mouse Work base blastocyst cell type chromatin remodeling design disease phenotype dosage embryonic stem cell fitness genome-wide histone modification human disease in vivo insight male mouse model nerve stem cell novel prevent public health relevance reproductive sarcoma transcriptome sequencing tumor tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The overarching goal of the three aims proposed for this project is to define genetic/epigenetic mechanisms that regulate the fine balance between human health and disease. My group identified CHD5 as a tumor suppressor mapping to 1p36-a region of the genome frequently deleted in human cancer. We defined Chd5 as a dosage-sensitive regulator of chromatin dynamics, and most recently, implicate Chd5 deficiency in male infertility and autism. The studies described in this proposal will build upon these discoveries by establishing novel models of human disease, assessing disease phenotypes, determining the mechanism(s) whereby Chd5 regulates chromatin to transcriptionally modulate disease pathways in normal cells, and elucidating how altered dosage of Chd5 affects chromatin dynamics in diseases such as cancer, infertility, and autism. The goal of Aim 1 is to generate mouse models with enhanced and compromised dosage of Chd5. This will be done using chromosome engineering, a genomic approach we used previously to establish mouse models with copy number variations found in cancer and autism. The goal of Aim 2 is to analyze existing Chd5 mouse models as well as the novel ones we generate in Aim 1 for phenotypes of cancer, infertility, and autism. This will be done using the quantitative in vivo functional assays we developed and used to define Chd5 as a suppressor of sarcoma development, as being vital for reproductive fitness, and as being essential in the brain. The goal of Aim 3 is to define the mechanism(s) whereby Chd5- mediated chromatin dynamics affects nuclear structure and regulates expression of disease pathways on a genome-wide scale. This will be accomplished by using microscopy to visualize H2B-eGFP patterns and by using RNA-seq, ChIP-seq, and bioinformatics to characterize global gene expression signatures, Chd5-bound loci, and covalent histone modifications in fibroblasts, spermatids, and neurons obtained from mice with altered dosage of Chd5. This project will establish unique models for several prevalent human diseases, will define the role of altered Chd5 dosage in disease phenotypes, and will provide new insights into the biological role of Chd5-mediated chromatin dynamics in health and disease. In addition, this work will elucidate epigenetic processes essential for preventing cancer, for ensuring fertility, and for normal brain function, presenting an unprecedented opportunity to identify convergence between cancer, infertility, and autism that may impact how these diseases are treated in the future.

描述（由申请人提供）：本项目提出的三个目标的总体目标是定义调节人类健康和疾病之间的精细平衡的遗传/表观遗传机制。我的小组将CHD 5确定为一种肿瘤抑制基因，定位于1 p36--人类癌症中经常缺失的基因组区域。我们将Chd 5定义为染色质动力学的剂量敏感调节剂，最近，涉及男性不育和自闭症中的Chd 5缺乏。本提案中描述的研究将以这些发现为基础，建立人类疾病的新模型，评估疾病表型，确定Chd 5调节染色质以转录调节正常细胞中的疾病途径的机制，并阐明改变剂量的Chd 5如何影响癌症，不育症和自闭症等疾病中的染色质动力学。目的1的目标是产生具有增强和折衷剂量的Chd 5的小鼠模型。这将使用染色体工程来完成，这是一种基因组方法，我们以前使用它来建立癌症和自闭症中发现的拷贝数变异的小鼠模型。目标2的目标是分析现有的Chd 5小鼠模型以及我们在目标1中生成的癌症，不育和自闭症表型的新模型。这将使用定量体内功能测定来完成我们开发并用于定义Chd 5作为肉瘤发展的抑制因子，作为生殖健康的重要因素，作为大脑中的必需因素。目的3的目标是定义Chd 5介导的染色质动力学影响核结构并在全基因组范围内调节疾病途径表达的机制。这将通过使用显微镜观察H2 B-eGFP模式，并通过使用RNA-seq，ChIP-seq和生物信息学来表征从Chd 5剂量改变的小鼠中获得的成纤维细胞，精子细胞和神经元中的全局基因表达特征，Chd 5结合位点和共价组蛋白修饰来实现。该项目将为几种流行的人类疾病建立独特的模型，将定义改变的Chd 5剂量在疾病表型中的作用，并将为Chd 5介导的染色质动力学在健康和疾病中的生物学作用提供新的见解。此外，这项工作将阐明预防癌症，确保生育能力和正常大脑功能所必需的表观遗传过程，为确定癌症，不育症和自闭症之间的趋同提供了前所未有的机会，这可能会影响这些疾病在未来的治疗方式。