Mapping heritable chromatin loop variants with allele-specific Hi-C analysis

通过等位基因特异性 Hi-C 分析绘制可遗传的染色质环变体图谱

基本信息

批准号：
10583721
负责人：
Alan D Attie
金额：
$ 68.75万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-21 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583721
关键词：
3-Dimensional ATAC-seq Address Affect Alleles Architecture Beta Cell Binding Binding Sites Biological Biological Models Biology Budgets CRISPR screen Cell Line Cell physiology Cells Chromatin Chromatin Loop Cohort Studies Collection Complex DNA DNA Sequence Data Diabetes Mellitus Disease Enhancers Epigenetic Process Etiology Euchromatin Event Future Gene Expression Genes Genetic Genetic Transcription Genetic Variation Genetic study Genome Genotype Goals Heritability Heterochromatin Heterozygote Hi-C Human Human Biology Human Genome Hybrids In Situ Inbred Strains Mice Insulin Antibodies Islets of Langerhans Knowledge Literature Mammalian Genetics Maps Methods Modeling Modernization Molecular Mouse Strains Multiomic Data Mus Names Nature Non-Insulin-Dependent Diabetes Mellitus Phenotype Physiological Population Property Publishing Quantitative Trait Loci Regulatory Element Reporting Research Resolution Role Sorting Structure Structure of beta Cell of islet Surveys Technology Time Tissues Transcriptional Regulation Translating Untranslated RNA Variant Visualization Work XCL1 gene bioinformatics tool cell type chromosome conformation capture cost data resource deep learning deep sequencing epigenome epigenomics functional genomics genetic variant genome wide association study genome-wide genomic data human disease improved in vivo insight invention islet male mammalian genome mouse genetics novel promoter single-cell RNA sequencing tool trait transcriptome

项目摘要

Project Abstract The organization of 3D architecture of mammalian genome is one of the major mysteries in biology. The invention of genome-wide chromosome conformation capture (3C) technologies, or Hi-C, have revealed a hierarchical 3D genome organization, including compartments corresponding to euchromatin and heterochromatin; with higher sequencing depth, Hi-C data further divided the genome into largely invariant topologically associated domains (TADs), which often serve as the boundary for long-range transcriptional regulation. Recently, with ultra-deep sequencing and improved analysis strategies at kilobase-scale resolution, Hi-C can identify chromatin loops within TADs connecting promoters and cis- regulatory elements in an unbiased fashion. Despite these progresses, an unexplored realm is the relationship between DNA sequence and 3D genome features, especially chromatin loops. It is important to elucidate how the transcription machinery translates the genetic variants into variable events at 3D genome levels and leads to transcriptional or physiological alterations. Here we propose to take an initial step solving the genetics of mammalian 3D genome using a panel of F1-hybrid mouse strains. This is enabled by our new Hi-C pipeline named DeepLoop which can sensitively and robustly identify kb- resolution chromatin loops from low-depth allele-resolved Hi-C data. In aim 1, we will generate comprehensive allele-specific maps of transcriptome, epigenome, and kilobase-resolution 3D genome in β-cells from a panel of 7 F1 mice generated from 8 founder strains, which cover nearly the entire spectrum of mouse genetic diversity. In aim 2, we will carry out integrative analyses to reveal the heritable cis- 3D regulatory modules in β-cells. We will also integrate the existing phenotype QTL, eQTL, and functional genomics data into our analysis. In aim 3, we will create a map of conserved 3D regulome between human and mouse β-cells to infer human biology from mouse genetic data. This project will reveal a large part of the genetics of 3D genome in mouse and serve as a launching pad for future human genome research.