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Mechanisms in Lamin A function in gene regulation

Lamin A 基因调控功能的机制

基本信息

批准号：
10152508
负责人：
Kohta Ikegami
金额：
$ 61.79万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10152508
关键词：
Affect Alanine Aspartate Back Binding Biochemical Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cell Cycle Stage Cell Line Cell Nucleus Cell physiology Cells ChIP-seq Chromatin Chromosome Structures Clustered Regularly Interspaced Short Palindromic Repeats DNA Damage Data Degenerative Disorder Development Disease Down-Regulation Enhancers Etiology Evolution Fibroblasts G0 Phase G1 Phase Gene Expression Gene Expression Profiling Gene Expression Regulation Genes Genetic Transcription Heterochromatin Human Intermediate Filaments Knock-out Knockout Mice Lamin Type A Maintenance Mass Spectrum Analysis Mechanical Stress Mediating Mitosis Molecular Mus Muscular Dystrophies Muscular dystrophy cardiomyopathy Mutation Nuclear Nuclear Lamina Nucleic Acid Regulatory Sequences Patients Phase Phenotype Physiological Physiological Processes Point Mutation Progeria Property Proteins Regulation Regulator Genes Regulatory Element Reporting Research Role S Phase Shapes Signal Transduction Site Skin Smooth Muscle Myocytes Specificity Structure Surveys Testing Thinking Tissues Transcription Coactivator Transcriptional Regulation Up-Regulation Vascular Smooth Muscle base cell type disease phenotype experimental study genome-wide genome-wide analysis human disease induced pluripotent stem cell insight mammalian genome mimetics mutant promoter response transcription factor transcriptome sequencing

项目摘要

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.

项目摘要核纤层蛋白A是脊椎动物特有的核纤层组分，其参与多种细胞凋亡。功能，包括细胞核的结构完整性，感受机械应力，细胞信号和染色质 organization.核纤层蛋白A的点突变导致一系列人类退行性疾病，统称为核纤层蛋白病，包括肌营养不良症、心肌病和一种称为早老症尽管进行了大量的研究，核纤层蛋白A影响细胞过程并导致细胞凋亡的机制仍不清楚。显著的和组织特异性的人类疾病表型仍不清楚。这个项目的核心假设是核纤层蛋白A部分作为转录因子发挥作用，特别是作为增强子的正调节剂，功能这是一种新的思考核纤层A功能的方法。这一假设是基于强大的初步数据显示，核纤层蛋白A与人类成纤维细胞中的基因启动子和增强子相关，核纤层蛋白A-增强子相互作用的丢失分别伴随着上调和下调。附近基因的调控。这项研究的总体目标是严格检验这一假设核纤层蛋白A在哺乳动物基因组的基因调控区起转录激活剂的作用。的 R21期的目的是鉴定核纤层蛋白A与基因相关的细胞周期阶段和细胞类型。调节区域，并验证核纤层蛋白A作为转录调节因子。R33阶段将探测核纤层蛋白A-增强子协会的机制和功能。具体而言，这一阶段将侧重于确定在调控区与核纤层蛋白A相互作用的蛋白质，确定核纤层蛋白A的亚核定位重要的协会和功能，并研究核纤层蛋白A-染色质相互作用的贡献，发展成核纤层蛋白病相关的心血管疾病。总之，该项目旨在证明Lamin A 在哺乳动物基因组中充当转录激活剂。如果得到证实，这种全新的作用机制将开辟新的研究途径，以了解脊椎动物的基因调控和特定机制，核纤层蛋白A在正常生理过程和疾病中的功能。它还将提供见解，核纤层蛋白A的进化和生化特性，使它既作为一个中间丝，用于基因调控的因子。所提出的实验将检验一个假设，该假设提供了一个直接的，对核纤层蛋白病的分子和物理表型的逻辑机制解释。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Differential Etv2 threshold requirement for endothelial and erythropoietic development.

DOI：
10.1016/j.celrep.2022.110881
发表时间：
2022-05-31
期刊：
CELL REPORTS
影响因子：
8.8
作者：
Sinha, Tanvi;van Bueren, Kelly Lammerts;Dickel, Diane E.;Zlatanova, Ivana;Thomas, Reuben;Lizama, Carlos O.;Xu, Shan-Mei;Zovein, Ann C.;Ikegami, Kohta;Moskowitz, Ivan P.;Pollard, Katherine S.;Pennacchio, Len A.;Black, Brian L.
通讯作者：
Black, Brian L.

Nuclear lamin phosphorylation: an emerging role in gene regulation and pathogenesis of laminopathies.