Mechanisms of Epigenetic Gene Silencing

表观遗传基因沉默的机制

基本信息

批准号：
8728366
负责人：
Kevin Pruitt
金额：
$ 2.04万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-06 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8728366
关键词：
Aberrant DNA Methylation Acetylation Address Antineoplastic Agents Binding Binding Proteins Chromatin Structure Clinical Trials Collaborations DNA DNA Methylation Data Deacetylase Deacetylation Decitabine Dysmyelopoietic Syndromes Epigenetic Process FDA approved Family Family member Gene Silencing Gene Targeting Genes Growth Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histones Hypermethylation Lead Life Link Lymphoma Malignant Neoplasms Methyl-CpG-Binding Protein 2 Methylation Molecular Patients Pattern Pharmaceutical Preparations Phase Property Protein Binding Refractory Role Sirtuins Solid Neoplasm Staging Therapeutic Transcriptional Regulation Tumor Suppressor Genes Vorinostat abstracting base cancer therapy design leukemia member novel promoter public health relevance tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Epigenetic alterations contribute to all stages of tumor progression and it is well recognized that aberrant DNA methylation and histone hypoacetylation of growth control genes and tumor suppressor genes directly contribute to malignancy. Because epigenetic changes are reversible, these alterations represent attractive targets for promising new anticancer agents and this property has been exploited recently for new therapies. While recent progress has lead to the FDA approval of the first two "epigenetic therapies" the mechanistic basis for their efficacy is poorly understood. This proposal will explore entirely new links between a relatively unexplored class of deacetylases (the sirtuins) and proteins that bind to methylated DNA (methyl-CpG binding proteins) in gene silencing. These advances could help explain why some solid tumors are refractory to the current epigenetic therapies and provide a more complete mechanism by which tumor suppressor genes (TSGs) become heritably silenced. Elucidating the molecular basis for this epigenetic silencing of growth control genes and TSGs is important for identifying novel anticancer therapies and we propose to do the following: Specific Aim 1 - Determine the role of methyl-CpG binding proteins in targeting SIRT1 to endogenous hypermethylated gene promoters. Specific Aim 2 - Determine the contribution of methyl-CpG binding proteins and SIRT1 in regulating chromatin structure at silenced growth control and tumor suppressor genes. Specific Aim 3 - Determine the functional significance of MeCP2 acetylation and deacetylation by SIRT1.

描述（由申请人提供）：表观遗传学改变有助于肿瘤进展的所有阶段，人们充分认识到，生长控制基因和肿瘤抑制基因的异常DNA甲基化和组蛋白低乙酸直接导致恶性肿瘤。由于表观遗传变化是可逆的，因此这些变化代表了有希望的新抗癌剂的有吸引力的靶标，并且该特性最近被利用用于新疗法。尽管最近的进展已导致FDA批准前两种“表观遗传疗法”，但其功效的机理基础知之甚少。该建议将探讨基因沉默中相对未开发的脱乙酰基酶（Sirtuins）类（Sirtuins）类（Sirtuins）的全新联系。这些进步可以帮助解释为什么某些实体瘤对当前的表观遗传疗法难治性，并提供了一种更完整的机制，肿瘤抑制基因（TSG）被遗传性沉默。阐明生长控制基因和TSG的这种表观遗传沉默的分子基础对于鉴定新型抗癌疗法非常重要，我们建议做以下操作：具体目标1-确定甲基-CPG结合蛋白在将SIRT 1靶向内源性高甲基化基因启动子中的作用。具体目标2-确定甲基-CPG结合蛋白和SIRT1在调节沉默的生长控制和肿瘤抑制基因下调节染色质结构的贡献。具体目标3-确定MECP2乙酰化和通过SIRT1脱乙酰化的功能意义。