Current Bioinformatics Seminar
Time: 11AM Tuesdays.
Venue: Davis Auditorium and Online
1 July 2025
This is a WEHI only event.The Next Phase: The analysis of haplotype resolved genomics data from immune cells
Hannah D CoughlanWEHI Bioinformatics
Regulation of gene expression is fundamental to establishing and maintaining cell identity. Much of this regulation is mediated by distal enhancers that control target genes through long-range DNA-DNA interactions, bringing enhancers and promoters into spatial proximity within the 3D genome. However, among the millions of such interactions across the genome, only a subset is truly regulatory and cell type specific, and the DNA sequence features that distinguish them remain poorly understood. Regulatory elements rely on short, conserved DNA motifs that serve as binding sites for transcription factors (TFs) where the precise nucleotide sequences is critical for TF recognition and binding. Single nucleotide polymorphisms (SNPs) within these motifs can disrupt TF binding affinity, leading to changes in chromatin accessibility and genome architecture. We have leveraged the millions of SNPs between the Castaneous (Cast) and C57BL/6 (B6) mouse strains as a source of nucleotide sequence variability. Using immune cells from Cast/B6 F1 offspring, where SNP locations are precisely known, we generated 3D genome (Hi-C) and chromatin accessibility (ATAC-seq) data. These SNPs enable the separation of genomic data into haplotypes (phasing), and analysis with a novel, statistically robust method based on edgeR revealed haplotype- and cell type-specific regions. We then performed motif enrichment analysis to identify critical DNA motifs disrupted by SNPs, resulting in altered transcription factor binding and subsequent changes in chromatin architecture and/or accessibility. Understanding how SNPs alter DNA motifs and influence transcription factor binding is critical for identifying which TFs are responsible for establishing and maintaining cell type defining epigenetics.