The impact of LINE-1 retrotransposons on life span, SASP, and telomeres in vivo

LINE-1逆转录转座子对体内寿命、SASP和端粒的影响

基本信息

批准号：
10431860
负责人：
Victoria Perepelitsa Belancio
金额：
$ 33.44万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10431860
关键词：
Adult Affect Age Animal Model Attenuated Biological Biological Assay Cancer Patient Cell Aging Cell physiology Cells Centenarian Cultured Cells Custom DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway Data Defect Deterioration Development Disease Dose Elements Functional disorder Future Gene Frequency Genetic Genetic Markers Genome Genomic DNA Genomic Instability Genomics Goals Health Heritability Human Human Genome In Vitro Individual Indolent Interleukin-6 Lead Length Location Long Interspersed Elements Longevity Lung Malignant neoplasm of prostate Measurable Messenger RNA Methods Modeling Mutation Normal tissue morphology Organ Phenotype Population Rat Transgene Rattus Reporting Retrotransposition Retrotransposon Risk Risk Factors Sampling Somatic Cell Source Specificity System Telomerase Telomere Shortening Testing Testis Time Tissues Transgenes Transgenic Organisms Variant cohort endonuclease genetic element genetic testing genome wide association study human tissue in vivo mRNA Expression mammalian genome middle age mutant novel offspring phenotypic biomarker predictive marker reference genome senescence telomere tissue culture transcriptome sequencing transgene expression

项目摘要

DNA damage accumulates with age in somatic tissues where it contributes to their dysfunction by causing mutations and cellular senescence. Senescent cells alter tissue microenvironment via secretion of proinflammatory molecules. DNA damage from endogenous or exogenous sources alone or in combination with defects in DNA repair pathways often decreases longevity. Long interspersed element-1, L1, an endogenous retrotransposon, contributes to genomic instability via retrotransposition and the induction of DNA double-strand breaks. Although endogenous L1 elements are expressed in normal human tissues and cause DNA damage and cellular senescence, whether L1 affects mammalian life span in vivo is unknown. Among the 500,000 L1 copies present in mammalian genomes only a few L1 loci are capable of causing further DNA damage. These L1 loci are often polymorphic for their presence in human genomes (pL1s) and are responsible for the bulk of L1-induced DNA damage. Although some individuals contain two or three times as many of these pL1 loci than others, the impact of this variation on human life span is not known. Our preliminary data generated using a transgenic rat model support that a functional L1 transgene increases levels of proinflammatory markers and shortens average and maximal lifespan in vivo. Our preliminary data also show that L1 endonuclease cuts telomeric sequences in vitro and may do so in vivo. We hypothesize that polymorphic L1 loci shorten mammalian lifespan in a dose-dependent manner by causing DNA damage that induces proinflammatory markers and/or telomere attrition. We will test this hypothesis by using custom transgenic rats to model variation in the number of functional L1s observed in the human population in order to study the effect of this variation on longevity in vivo. We will also use DNA samples collected from average and long-lived (>99 year old) individuals to determine their pL1 content and whether the number of pL1s per genome correlates with life span. We will use in vitro and tissue culture approaches to determine whether L1 contribution to an increase in SASP markers or telomere attrition could be a plausible mechanism(s) by which L1 may impact longevity. Combined our findings would provide a currently lacking experimental support for pL1 impact on longevity in vivo and novel mechanisms underlying this effect.

DNA 损伤随着年龄的增长在体组织中积累，通过导致体组织功能障碍突变和细胞衰老。衰老细胞通过分泌改变组织微环境促炎分子。单独或组合的内源或外源 DNA 损伤 DNA 修复途径缺陷通常会缩短寿命。长散布元素-1，L1，an 内源性逆转录转座子，通过逆转录转座和 DNA 诱导导致基因组不稳定双链断裂。尽管内源性 L1 元件在正常人体组织中表达并导致 DNA损伤和细胞衰老，L1是否影响哺乳动物体内寿命尚不清楚。其中哺乳动物基因组中存在 500,000 个 L1 拷贝，只有少数 L1 位点能够产生更多 DNA 损害。这些 L1 位点因其在人类基因组 (pL1) 中的存在而通常具有多态性，并且负责对于大部分 L1 诱导的 DNA 损伤。尽管有些人含有两到三倍的这些 pL1 位点与其他位点相比，这种变异对人类寿命的影响尚不清楚。我们的初步数据使用转基因大鼠模型产生的结果支持功能性 L1 转基因可提高促炎标记物并缩短体内平均和最大寿命。我们的初步数据还显示 L1 核酸内切酶在体外切割端粒序列，并且在体内也可能如此。我们假设多态性 L1 位点通过引起 DNA 损伤，以剂量依赖性方式缩短哺乳动物的寿命诱导促炎标记物和/或端粒磨损。我们将使用自定义测试这个假设转基因大鼠模拟在人群中观察到的功能性 L1 数量的变化，以便研究这种变异对体内寿命的影响。我们还将使用从平均水平和长寿（> 99岁）个体以确定其pL1含量以及每个人的pL1数量是否基因组与寿命相关。我们将使用体外和组织培养方法来确定 L1 是否对 SASP 标记或端粒磨损增加的贡献可能是一种合理的机制，通过该机制 L1 可能会影响寿命。综合我们的发现将为 pL1 提供目前缺乏的实验支持对体内寿命的影响以及这种效应背后的新机制。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Analysis of epigenetic features characteristic of L1 loci expressed in human cells.

分析人类细胞中表达的 L1 基因座的表观遗传特征。

DOI：
发表时间：
2022-02-28
期刊：
影响因子：
14.9
作者：
Freeman, Benjamin;White, Travis;Kaul, Tiffany;Stow, Emily C;Baddoo, Melody;Ungerleider, Nathan;Morales, Maria;Yang, Hanlin;Deharo, Dawn;Deininger, Prescott;Belancio, Victoria P
通讯作者：
Belancio, Victoria P

Identification of charged amino acids required for nuclear localization of human L1 ORF1 protein.

鉴定人 L1 ORF1 蛋白核定位所需的带电氨基酸。

DOI：
发表时间：
2019
期刊：
影响因子：
4.9
作者：
Freeman, B T;Sokolowski, M;Roy;Smither, M E;Belancio, V P
通讯作者：
Belancio, V P

SCIFER: approach for analysis of LINE-1 mRNA expression in single cells at a single locus resolution.

SCIFER：以单基因座分辨率分析单细胞中 LINE-1 mRNA 表达的方法。

DOI：
发表时间：
2022-08-26
期刊：
影响因子：
4.9
作者：
Stow, Emily C;Baddoo, Melody;LaRosa, Alexis J;LaCoste, Dawn;Deininger, Prescott;Belancio, Victoria
通讯作者：
Belancio, Victoria

Comparative analysis on the expression of L1 loci using various RNA-Seq preparations.

使用各种 RNA-Seq 制剂对 L1 位点的表达进行比较分析。

DOI：
发表时间：
2020
期刊：
影响因子：
4.9
作者：
Kaul, Tiffany;Morales, Maria E;Sartor, Alton O;Belancio, Victoria P;Deininger, Prescott
通讯作者：
Deininger, Prescott

Organ-, sex- and age-dependent patterns of endogenous L1 mRNA expression at a single locus resolution.

单基因座分辨率下内源性 L1 mRNA 表达的器官、性别和年龄依赖性模式。

DOI：
发表时间：
2021
期刊：
影响因子：
14.9
作者：
Stow, Emily C;Kaul, Tiffany;deHaro, Dawn L;Dem, Madeleine R;Beletsky, Anna G;Morales, Maria E;Du, Qianhui;LaRosa, Alexis J;Yang, Hanlin;Smither, Emily;Baddoo, Melody;Ungerleider, Nathan;Deininger, Prescott;Belancio, Victoria P
通讯作者：
Belancio, Victoria P