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Reprogramming of cardiac genome by Smyd1 in hypertrophy and failure

Smyd1 在肥厚和衰竭中对心脏基因组进行重编程

基本信息

批准号：
8528045
负责人：
Sarah Franklin
金额：
$ 24.9万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8528045
关键词：
Address Adult Affect Animals Architecture Attention Binding Biochemistry Birth Budgets Cardiac Cardiac Myocytes Cause of Death Cell model Cells Characteristics Chromatin Chromatin Structure Clinical Co-Immunoprecipitations DNA DNA Packaging DNA Sequence Data Development Disease Embryo Enzymes Estrogen Receptors Event Excision Exhibits Failure Family Family member Figs - dietary Future Gene Expression Genes Genome Genomics Goals Grant Heart Heart Diseases Heart Hypertrophy Heart failure Heat-Shock Proteins 90 Higher Order Chromatin Structure Histone H3 Histones Human Hypertrophy Image Intervention Life Mass Spectrum Analysis Measures Messenger RNA Methylation Microscopy Modification Morphology Mus Muscle Muscle Cells Myoblasts Myocardium Nuclear Nuclear Proteins Nucleosomes Performance Phenotype Physiology Positioning Attribute Post-Translational Protein Processing Proteins Proteomics Regulation Role Site Specificity Stimulus Tail Tamoxifen Technology TimeLine Transcript Transgenic Mice Western Blotting base cell type chromatin remodeling constriction genome-wide histone methyltransferase in vivo insight next generation overexpression pressure

项目摘要

PROJECT SUMMARY/ABSTRACT It is now appreciated that genomes are dynamic and that selective packing of DNA governs the expression of distinct sets of genes in a cell. The wrapping of DNA around nucleosomes and its organization into higher order structures is fundamentally influenced by chromatin remodeling enzymes. These enzymes selectively position nucleosomes along the DNA strand and influence the interaction of histones with DNA by modifying the amino terminal tails of histones. Gross changes in chromatin structure are most prominent during development and influence cell fate by establishing cell-type-specific gene expression. Changes in chromatin structure have also been observed during disease and disruption of chromatin remodeling enzymes has been implicated in cardiac hypertrophy. However, a clear picture of the protein networks that modulate chromatin architecture in the heart is needed to understand how gene expression is reprogrammed on a genome-wide scale during disease. Although the post-translational modification (PTM) of histones has been well established, the enzymes responsible for the selective addition and removal of these regulatory marks have only begun to be characterized. A newly emerging family of histone methyltransferases (HMTs) is called Smyd. Germline deletion of the muscle-restricted family member, Smyd1, leads to embryonic lethality due to impaired cardiac differentiation. Consistent with this observation, overexpression of Smyd1 in muscle precursor cells led to accelerated differentiation. Despite these intriguing insights into the role of Smyd1 during development, its endogenous localization, regulation and role in cardiac disease are unknown. My preliminary data demonstrate increased Smyd1 abundance during heart failure and establish the approaches to determine its activity, intracellular localization and mechanisms of action in this application. The short term goal of this application is to understand the role of Smyd1 in the adult myocardium and to characterize its downstream targets during heart failure. The long term goal of this project is to integrate these concepts to understand the factors that confer targeting specificity to Smyd1 in the cardiac genome. This application leverages state-of-the-art proteomics, animal physiology, biochemistry, imaging and next generation sequencing technology to advance our understanding of heart failure. Our approach will provide fundamental insights into the activation and regulation of HMTs, as well as the mechanisms that confer specificity in their targeting of the genome. The significance to the clinical realm is to provide a mechanistic basis for how the genome is reprogrammed with disease, such that future interventions can target specific chromatin remodeling events therapeutically.

项目总结/文摘