Mechanisms of Epigenetic Gene Silencing

描述(申请人提供)：表观遗传改变有助于肿瘤进展的所有阶段，众所周知，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酰化直接导致恶性肿瘤。由于表观遗传改变是可逆的，这些改变是有希望的新抗癌药物的诱人靶点，这一特性最近已被用于新的治疗方法。虽然最近的进展导致FDA批准了前两种“表观遗传疗法”，但其疗效的机制基础尚不清楚。这项提议将探索一类相对未知的脱乙酰酶(Sirtuins)和在基因沉默中与甲基化DNA结合的蛋白质(甲基CpG结合蛋白)之间的全新联系。这些进展有助于解释为什么一些实体肿瘤对当前的表观遗传疗法无效，并提供了一种更完整的机制，使肿瘤抑制基因(TSG)变得遗传性沉默。阐明这种生长控制基因和TSGs表观遗传沉默的分子基础对于确定新的抗癌治疗方法非常重要，我们建议做以下工作：特定目的1-确定甲基-CpG结合蛋白在靶向SIRT1内源性高甲基化基因启动子中的作用。特定目的2-确定甲基CpG结合蛋白和SIRT1在沉默的生长控制和肿瘤抑制基因中调节染色质结构的作用。特定目的3-确定MeCP2乙酰化和SIRT1去乙酰化的功能意义。

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.