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Accelerated DNA Methylation Alterations in Hutchinson-Gilford Progeria Syndrome

Hutchinson-Gilford 早衰综合症中 DNA 甲基化的加速改变

基本信息

批准号：
10780718
负责人：
PETER W LAIRD
金额：
$ 78.62万
依托单位：
VAN ANDEL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10780718
关键词：
Acceleration Aging Automobile Driving Biological Models Catalytic Domain Cell Aging Cell Culture Techniques Cell Nucleus Cell division Cell physiology Cells Childhood Chromatin Communities Cytosine DNA Damage DNA Methylation DNA Modification Methylases DNA analysis DNA biosynthesis Data Dioxygenases Elements Epigenetic Process Event Experimental Designs Fibroblasts Gene Expression Genes Genetic Genome Genomic Imprinting Genomics Heterochromatin Human LMNB1 gene Longevity Methods Mitosis Mitotic Modeling Monitor Morphology Mus Muscular Atrophy Mutation Nuclear Nuclear Lamin Nuclear Lamina Nuclear Protein Outcome Patients Pattern Phenotype Play Polycomb Population Premature aging syndrome Production Progeria Protein Export Pathway Protein Isoforms Publishing RNA-Directed DNA Polymerase Recording of previous events Repression Research Resolution Role Smooth Muscle Smooth Muscle Myocytes Structure Symptoms Syndrome Telomerase Testing Tissues Validation X Inactivation bisulfite sequencing cost effective design experimental study farnesylation gain of function innovation lentivirally transduced methylation pattern methylome mouse genome mouse model mutant normal aging novel therapeutic intervention overexpression oxidative damage prelamin A rare genetic disorder replication stress senescence spatiotemporal vector whole genome

项目摘要

PROJECT SUMMARY / ABSTRACT Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by the rapid onset of premature aging beginning in childhood. The condition is caused by a mutation in the nuclear lamin LMNA gene, which leads to the production of a dominant gain-of-function isoform of the protein, called progerin. Progerin causes major disruptions to nuclear morphology and function, including nuclear protein export and mitosis, replication stress, and contributes to increased DNA damage as well as the loss of heterochromatin and dysregylation of other epigenetic marks, including cytosine-5 DNA methylation. We have recently provided direct experimental evidence that aging-associated loss of DNA methylation at nuclear lamina-attached regions of the genome is a direct consequence of cell division-associated DNA replication. We used this principle to develop an epigenetic mitotic clock, called RepliTali, which provides a reliable estimate of cellular replicative history. We hypothesize that altered DNA methylation patterns in patients with HGPS may contribute actively to the severely accelerated aging observed in patients with HGPS. Here, we propose to conduct high- resolution analyses of DNA methylation alterations in serially cultured HGPS cells and to investigate whether we can extend the lifespan of HGPS model systems by manipulating DNA methylation patterns. In Specific Aim 1 we will define DNA methylation dynamics in serially cultured HGPS fibroblasts from early passage through replicative senescence using cost-effective Infinium DNA methylation arrays. In Specific Aim 2 we will conduct high-resolution single-cell methylome analyses at key stages of HGPS fibroblast culture to detect arising aberrations and delineate population transitions. We have developed a single-cell whole-genome bisulfite sequencing (sc-WGBS) method that delivers genomic coverage far superior to any other published sc-WGBS methods. In Specific Aim 3 we will investigate whether DNA methylation manipulation can extend lifespan in HGPS models. In Aim 3A we will test whether overexpression of DNA methylation writers and erasers increases the replicative lifespan of HGPS fibroblasts. In Aim 3B, we will target DNA methyltransferase overexpression to arterial smooth muscle cells in an HGPS mouse model to investigate whether this reduces arterial smooth muscle loss and extends lifespan. We will monitor DNA methylation changes in this mouse model using a new cost-effective DNA methylation array. We present extensive and compelling preliminary data that demonstrates both the feasibility and relevance of the proposed aims. The outcome of this proposed research could have important impacts on our understanding of the contribution of DNA methylation alterations to HGPS phenotypes, potentially opening avenues for new therapeutic approaches to treat progeria. In addition, this study could shed light on similar mechanisms operating at a longer timescale in normal aging.

项目摘要/摘要