Mitochondrial DNA, Nuclear DNA Methylation, and Cardiometabolic Disease Traits

线粒体 DNA、核 DNA 甲基化和心脏代谢疾病特征

• 批准号: 10475148
• 负责人: Chunyu Liu
• 金额: $ 58.3万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475148
• 关键词: Affect; Aging; Anabolism; Applications Grants; Blood; Blood Glucose; Body mass index; CRISPR/Cas technology; Cardiometabolic Disease; Cardiovascular Diseases; Cell Line; Cells; Cellular Metabolic Process; Communities; DNA Methylation; DNA biosynthesis; DNA copy number; DNA-Directed DNA Polymerase; Databases; Development; Diagnosis; Disease; Elderly; Energy Metabolism; Etiology; European; Event; Fasting; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genome; Genotype; Heart; Hybrids; Impairment; Knock-out; Knowledge; Link; Maintenance; Measures; Mediating; Mediation; Metabolic syndrome; Methylation; Mitochondria; Mitochondrial DNA; Modality; Modeling; Modification; Molecular; Mouse Strains; Mus; Mutation; National Heart, Lung, and Blood Institute; Nuclear; Obesity; Participant; Pathway interactions; Play; Prevention; Production; Proteins; Reporting; Research; Research Personnel; Research Project Grants; Resources; Risk Factors; Role; Site; System; Testing; Tissues; Trans-Omics for Precision Medicine; Transcript; Translations; Whole Blood; base; cardiovascular disorder risk; cohort; disorder risk; epigenome-wide association studies; factor A; gene network; gene regulatory network; genetic epidemiology; genome sequencing; heteroplasmy; human disease; low density lipoprotein triglyceride; methylation pattern; mouse model; mtTF1 transcription factor; multiple omics; open source; peripheral blood; programs; protein protein interaction; response; trait; transcription factor; whole genome

PROJECT SUMMARY Energy metabolism plays a critical role in human disease. Mitochondria, the energy powerhouses of the cell, have their own genome (mtDNA) which is present up to thousands of copies per cell. mtDNA encodes genes for proteins of energy metabolism. We (led by Liu, PI of this application) recently discovered that lower mtDNA copy number in whole blood is an independent predictor for higher levels of cardiovascular disease (CMD) risk factors in ~60,000 participants from multiple ancestries. For example, one standard deviation of decrease in mtDNA copy number was associated with increased odds of obesity (OR=1.15, p=8e-31) and metabolic syndrome (OR=1.14, p=1e-32), as well as with increased levels of several quantitative traits defining these diseases. Despite these findings, the molecular basis underlying the association of mtDNA with CMD is unclear because the nuclear genome (nDNA) also encodes many of the proteins engaged in mitochondrial energy production and biosynthesis, and thus, maintenance of mitochondrial function requires extensive coordination of mtDNA and nDNA. A mouse hybrid nDNA-mtDNA system was developed. Using this model, the researchers found differential nDNA methylation, gene expression, and cellular adaptive response in hybrid mice of identical nDNA, but with different mtDNA background. Additionally, we (led by Arking, Co-I of this application) identified several significant DNA methylation sites associated with mtDNA copy number. In addition, experimental modification of mtDNA copy number through knockout via CRISPR-Cas9 of TFAM, a regulator of mtDNA replication, demonstrated that modulation of mtDNA copy number directly drives changes in nDNA methylation of specific CpGs and gene expression of nearby transcripts. Based on these previous studies in mouse model and our own research, we hypothesize that methylation and gene expression of nDNA mediate the effects of mtDNA on cardiometabolic disease traits. In this proposed proposal, we will leverage existing resources, including whole genome sequencing and multi-omics in six large cohorts of multiple ancestries; we will rigorously test our hypothesis by pursuing four specific aims. In Aim 1 and Aim 2, we will perform association analyses to identify mtDNA-associated nDNA methylation sites and gene expression levels, respectively. mtDNA features include mtDNA homoplasmic and heteroplasmic mutations, and mtDNA copy number. In Aim 3, we will investigate whether nDNA methylation and/or gene expression mediates the effects of mtDNA copy number and heteroplasmy on continuous cardiometabolic disease traits. In Aim 4, we will perform integrative analyses to identify gene regulation networks underlying mtDNA and cardiometabolic disease traits. We will also functionally test the impact of mtDNA on these gene networks via edited cell lines (e.g., via CRISPR-Cas9 system). The body of knowledge generated by this research project will deepen our understanding of molecular mechanisms underlying mtDNA and cardiometabolic diseases, which will ultimately facilitate the development of new modalities for the diagnosis, prevention, and treatment of cardiometabolic diseases.

项目总结