Wednesday, February 5, 2025
2/5/2025
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.
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