Mechanisms in Lamin A function in gene regulation

项目总结 层粘连蛋白A是脊椎动物特有的核膜成分，与多种细胞因子有关。 功能，包括核的结构完整性、感知机械应力、细胞信号和染色质 组织。层粘连蛋白A的点突变导致一系列人类退行性疾病，统称为 椎板病包括肌营养不良症、心肌病和一种称为 早衰症。尽管进行了密集的研究，但拉米素A影响细胞过程并导致 显著的和特定于组织的人类疾病表型仍然不清楚。这个项目的中心假设是 Lamin A部分作为转录因子发挥作用，特别是作为增强子的正向调节器 功能。这是对拉明A函数的一种新的思考方式。这一假设是建立在强有力的初步基础上的 数据显示，Lamin A与人类成纤维细胞中的基因启动子和增强子相关联，并获得了 而Lamin A-增强子相互作用的丧失分别伴随着上调和下调。 对邻近基因的调控。这项拟议研究的总体目标是严格检验这一假设。 Lamin A在哺乳动物基因组的基因调控区域扮演转录激活剂的角色。这个 R21期的目的是确定Lamin A与基因相关的细胞周期阶段和细胞类型 并验证Lamin A是否起转录调节作用。R33阶段将探测 层粘连蛋白A-增强子联合的机制和功能。具体地说，这一阶段将侧重于确定 与Lamin A在调节区相互作用的蛋白质，识别Lamin A的亚核定位 的关联和功能，并研究Lamin A-染色质相互作用对 椎板病相关心血管疾病的发展。总而言之，该项目旨在证明拉明·A 在哺乳动物基因组中起转录激活剂的作用。如果得到证实，这种全新的行动机制 将为理解脊椎动物特有的基因调控机制和基因调控机制开辟新的研究途径 Lamin A在正常生理过程和疾病中的作用。它还将为 拉米素A的进化及其生化特性使其既可以作为中间纤维又可以作为 用于基因调控的因子。提出的实验将检验一个假设，该假设提供了一个直接和 椎板病的分子和物理表型的逻辑机制解释。

PROJECT SUMMARY Lamin A is a vertebrate-specific nuclear lamina component that has been implicated in a variety of cellular functions, including structural integrity of the nucleus, sensing mechanical stress, cell signaling, and chromatin organization. Point mutations in Lamin A cause a spectrum of human degenerative disorders collectively called laminopathies including muscular dystrophies, cardiomyopathies, and a multisystem disorder known as progeria. Despite intense study, the mechanisms by which Lamin A affects cellular processes and causes such striking and tissue-specific human disease phenotypes remain unclear. The central hypothesis of this project is that Lamin A functions in part as a transcription factor, specifically as a positive modulator of enhancer function. This is a new way of thinking about Lamin A function. This hypothesis is based on strong preliminary data, showing that Lamin A associates with gene promoters and enhancers in human fibroblasts and that gains and losses of Lamin A-enhancer interactions were accompanied respectively by up-regulation and down- regulation of nearby genes. The overall objective of this proposed research is to rigorously test the hypothesis that Lamin A acts as an transcriptional activator at gene regulatory regions in the mammalian genome. The aim of the R21 phase is to identify the cell-cycle stages and cell types in which Lamin A associates with gene regulatory regions and to verify that Lamin A acts as transcription regulator. The R33 phase will probe the mechanism and function of Lamin A-enhancer associations. Specifically, this phase will focus on identifying proteins interacting with Lamin A at regulatory regions, identifying subnuclear localization of Lamin A important for the associations and function, and investigating the contribution of Lamin A-chromatin interactions to development of laminopathy-related cardiovascular disease. Altogether, the project aims to prove that Lamin A acts as a transcription activator in the mammalian genome. If proven, this entirely new mechanism of action will open new research avenues to understanding vertebrate-specific mechanisms of gene regulation and the function of Lamin A in normal physiological processes and disease. It would also provide insights to the evolution of Lamin A and the biochemical properties that allow it to act as both an intermediate filament and a factor used in gene regulation. The experiments proposed would test a hypothesis that offers a direct and logical mechanistic explanation for the molecular and physical phenotypes of laminopathies.