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Functions and Mechanisms of Epigenetic Allelic Effects in the Brain

大脑表观遗传等位基因效应的功能和机制

基本信息

批准号：
9807101
负责人：
Chris Gregg
金额：
$ 22.88万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9807101
关键词：
Address Adolescent Adult Affect Age Alleles Behavior Behavioral Brain Brain Diseases Brain region Candidate Disease Gene Cell Lineage Cells DNA Repair DNA Repair Gene DNA Sequence Alteration Data Development Developmental Gene Diagnostic Disease Economic Burden Embryo Epigenetic Process Epitopes Expression Profiling Female Foundations Future Gene Expression Gene Expression Regulation Generations Genes Genetic Risk Genetic Variation Genomic Imprinting Genomics Genotype Goals Heterozygote Homozygote Image Individual International Knowledge Lead Link Measures Mental Health Mental disorders Modeling Mosaicism Mus Mutate Mutation NMDA receptor A1 National Institute of Mental Health Nature Neuroglia Neurologic Neurons Patients Pattern Phenotype Play Population Primates Process Proteins Public Health Publications RNA Reporter Research Risk Role Shapes Switch Genes Synapses Testing Therapeutic Time Weaning X Inactivation brain cell cell type cohort differential expression improved in vivo mutant neuropsychiatric disorder novel novel therapeutic intervention postnatal social synaptic function

项目摘要

PROJECT SUMMARY For reasons that are unclear, neuropsychiatric disorders are phenotypically variable and often the same gene is implicated in different disorders. Our limited understanding of the link between genotype and phenotype has stalled the development of improved diagnostics and therapeutics. An NIMH strategic priority to address this involves deepening our understanding of regulatory factors that alter gene expression and are important for brain processes relevant to mental illness. Little is known about allele-specific epigenetic effects that could interact with heterozygous genetic mutations to influence phenotypic variance and mental health. The goal of this study is to uncover novel epigenetic effects at the allele, protein and cellular level in the brain. In a recent publication in Neuron, we uncovered thousands of genes that differentially express their maternal and paternal alleles at the RNA level in vivo in a developmentally regulated manner in the mouse and primate brain. We refer to these phenomena as differential allele expression effects (DAEEs). DAEEs are not due to genetic variation or genomic imprinting and involve random monoallelic expression in subpopulations of brain cells. We found that DAEEs interact with heterozygous mutations to cause mosaics of monoallelic brain cells that differentially express mutant versus wildtype alleles at the RNA level. Currently, we do not know whether DAEEs result in random monoallelic expression at the protein level and involve stable or dynamic allelic expression states in a cell over time. Moreover, it is unclear when DAEEs arise during brain development, whether specific cell types are consistently impacted for different genes and whether DAEEs can interact with heterozygous mutations to shape phenotypic effects. Therefore, we propose an exploratory study that will begin to address these important gaps in our knowledge and set the foundations for future functional and mechanistic studies of DAEEs in shaping mental health. Aim 1 will determine the expression profiles of DAEEs at the protein and cellular level in the brain for different functional classes of genes with distinct developmental patterns of epigenetic allelic effects, revealing monoallelic and biallelic brain cell populations at the protein level and testing for stable versus dynamic allelic states in individual cells. Aim 2 will identify candidate autosomal genes with stable random monoallelic expression effects that shape the impact of heterozygous mutations on specific behavioral and neurological phenotypes. Our study is significant because it addresses fundamental gaps in our knowledge and will uncover novel stable and/or dynamic epigenetic allelic effects on brain gene expression at the protein level. The results will lay foundations to test specific functional models that are expected to reveal mechanisms by which gene regulation at the allele and cellular level in the brain contributes to phenotypic variance and risks for mental illness.

项目总结