A Trim28-ERV axis drives phenotypic variation in obesity

Trim28-ERV 轴驱动肥胖的表型变异

• 批准号: 10586530
• 负责人: John Andrew Pospisilik
• 金额: $ 60万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586530
• 关键词: Adipocytes; Animal Model; Animals; Binding; Buffers; Cells; Characteristics; Chromatin; Communities; Competitive Binding; Complex; Coupled; DNA Methylation; Data; Development; Disease; Disease Outcome; Endogenous Retroviruses; Enhancers; Environment; Epigenetic Process; Equilibrium; Etiology; Exhibits; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Epistasis; Genome; Genomics; Hepatocyte; Heterogeneity; Heterozygote; Human; Inbreeding; Incidence; Individual; Lead; Measures; Mediating; Metabolic Diseases; Methylation; Mus; Obesity; Other Genetics; Pathway interactions; Phenotype; Protein Binding Domain; Proteins; Repression; Research; Severities; Testing; Tissues; Translating; Twin Multiple Birth; Variant; Work; Zinc Fingers; disease heterogeneity; epigenetic silencing; epigenomics; experimental study; in vivo; mRNA Expression; male; methylation pattern; non-genetic; novel; promoter; recruit; transcriptome sequencing

Modified Project Summary/Abstract Section Estimates from twin and inbred animal models suggest that up to 50% of metabolic disease heterogeneity is due to something other than genetics or the environment. We previously discovered that Trim28 is a master regulator of non-genetic, non-environmental phenotypic heterogeneity; demonstrated that Trim28 buffers against a unique (bistable) epigenetic obesity in isogenic Trim28+/D9 mice; and identified a comparable TRIM28-associated mRNA expression signature in human obesity. Individuals at the obese, epigenetically “ON” end of the spectrum are characterized by dysregulation of Trim28-sensitive loci, including endogenous retroviruses (ERVs). Trim28-normally interacts with KZFPs to keep ERVs in a stable, fully silenced state throughout development. However, a subset of ERVs partially escape this silencing and become variably methylated (VM-ERVs), which translates into variable levels of repression/activation, subsequent variability in neighboring gene expression, and ultimately phenotypic variation. Our preliminary data indicate that VM-ERVs have sequence content allowing them to be bound by Zinc-Finger-CxxC (ZF-CxxC) domain containing proteins, thereby protecting these loci from methylation. We hypothesize that activation vs silencing at VM-ERV loci is controlled by a competition between KZFP/Trim28 and ZF-CxxC binding, and that TRIM28-sensitive VM-ERV expression is a significant driver of unexplained phenotypic variation and metabolic disease heterogeneity. We will test these hypotheses through three independent Aims. In Aim 1, we will define the epigenomic characteristics of ERVs in hepatocytes and adipocytes to identify the epigenomic and genomic features that define VM-ERVs. In Aim 2, we will profile binding of specific ZF-CxxC proteins (CFP1 and TET1) to prove that these proteins gain a competitive binding advantage as Trim28 levels are reduced and demonstrate that ZF-CxxC – KZFP/Trim28 competition triggers epigenetic variability at VM-ERVs. In Aim 3, we will determine if VM-ERV activation is coupled to metabolic disease heterogeneity. We expect this project will identify Trim28/ZF-CxxC competition as a novel mechanism governing the variable silencing at ERVs and provide the research community with a comprehensive list of target proteins and pathways to study and begin understanding how VM-ERV dysregulation triggers and/or influences complex disease etiology.

修改的项目摘要/摘要部分 双胞胎和无限模型的估计表明，我们以前发现Trim28是非基因的非企业表型异质体的主要调节剂。 D9小鼠在肥胖症的肥胖症中的表达，谱的末端具有28个敏感的基因座的失调（VM-RVS），它转化为可变的固定/激活水平，我们的初步PIC变化。 ，从而保护这些LOM甲基化。疾病异质性。我们将测试三个独立的目标。 theteins降低了Trim28水平的竞争性结合该项目将确定TRIM28/ZF-CXXC MPETITION作为诺卡派政府机构管理ERV的可变沉默，并为研究社区提供全面的目标蛋白质和研究途径，以研究和开始如何理解VM-Vers的失调障碍和/或/或/或影响复杂疾病的病因。