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Linking Psychiatric Genetics to Cell-Type Specific Enhancer Function

将精神病遗传学与细胞类型特异性增强子功能联系起来

基本信息

批准号：
9751975
负责人：
Diane Elaine Dickel
金额：
$ 71.91万
依托单位：
UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
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：
2018-08-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751975
关键词：
Affect Biological Assay Brain Brain Mapping Brain region Catalogs Cells ChIP-seq Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Code Collection DNA Data Data Set Development Disease Distant Embryo Engineering Enhancers Etiology Funding Gene Expression Gene Expression Alteration Gene Transfer Techniques Genetic Genetic Transcription Genetic study Genome Gold Histologic Human Human Genetics Human Genome Individual Label Lead Link Linkage Disequilibrium Maps Mediating Mental disorders Methods Molecular Mus Nervous System Physiology Neuroanatomy Neurobiology Neurons Pattern Phenotype Population Proteins Reporting Resolution Resources Risk Scheme Series Site Specificity Structure Testing Time Tissues Transgenic Mice United States National Institutes of Health Untranslated RNA Validation Variant Work base brain tissue cell type cohort comparative disorder risk epigenomics experimental study follow-up functional genomics genome sequencing genome wide association study improved in vivo in vivo evaluation insight member neuropsychiatric disorder novel novel strategies predictive test prenatal psychogenetics risk variant single-cell RNA sequencing therapy development transcriptome whole genome

项目摘要

PROJECT SUMMARY Genome-wide association studies (GWAS) provide robust statistical evidence linking individual sequence variants to increased risk of disease. However, the majority of GWAS-identified risk variants identified to date, including those for psychiatric disorders, do not affect protein-coding sequence but instead map to noncoding DNA. GWAS alone yield little direct insight into the mechanisms by which these variants confer increased risk. It is widely assumed that many affect the function of distant-acting transcriptional enhancers, but the historically poor annotation of noncoding functional sequences in the human genome has rendered their interpretation challenging. Over the past decade, our lab and others made substantial progress toward identifying enhancers in the genome at scale. For example, our group has used ChIP-seq from mouse and human brain tissues to identify initial collections of developmentally active brain enhancers. Furthermore, as members of the ENCODE consortium, we generated the first high-resolution time series mapping the brain chromatin landscape throughout mouse prenatal development. These resources, along with complementary data from NIH-funded consortia, are now available to aid in the interpretation of GWAS results. Here we propose to bridge the current gap between noncoding GWAS findings and mechanistic understanding of psychiatric disorder etiology. We will couple extensive pre-existing epigenomic resources to cutting-edge mouse engineering and single cell-resolution transcriptome analyses in order to understand how enhancer variants contribute to psychiatric disease risk. Specifically we will: 1) Perform an integrative analysis of psychiatric disorder GWAS results and epigenomically predicted brain enhancers to identify regulatory sequences that harbor disease-associated variants and prioritize them for functional validation, 2) Use high-throughput mouse transgenic assays to validate predicted enhancers in vivo and determine the exact brain regions in which they are active, 3) Use single cell RNA-sequencing of transgenic mice to determine the exact cell type(s) in which a brain enhancer functions, and 4) Use these in vivo functional genomic methods to uncover whether and how disease-associated sequence variants impact the cell type-specific activity of each enhancer. As whole genome sequencing of psychiatric disease cohorts continues to progress, we will also assess variants from those studies. In combination, our work will uncover how noncoding disease-associated variants alter enhancer function in vivo, link noncoding GWAS findings to specific cell types, and provide a unique panel of well-characterized enhancers that can be used to label discrete neuronal cell populations for further downstream characterization. The results will substantially improve our mechanistic understanding of how noncoding sequence changes contribute to mental illness and provide entry points for potential downstream therapies.

项目总结