WEHI Wednesday Seminar hosted by Professor Gordon Smyth

Dr Hannah Coughlan
Senior Research Officer – Smyth Laboratory, Technological Sciences division, WEHI

A Twist of Fate: Untangling the Epigenetic Rules of gene regulation

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session

Every nucleated cell in the body carries a (near) identical DNA sequence. During development thousands of distinct cellular identities and functions are encoded by this DNA. This remarkable cellular diversity is partly achieved via epigenetic regulation of gene expression. A critical layer of this regulation is driven by the 3D architecture of the genome: distal enhancers are drawn into three-dimensional proximity with gene promoters to regulate gene expression. These interactions are facilitated by transcription factors (TFs) which recognise short, conserved DNA motifs that serve as binding sites, where the precise nucleotide sequence is critical for TF recognition and binding. However, despite the perceived importance of TFs in facilitating lineage-specific 3D genome architecture, only a handful of TFs have been confirmed as cell type specific regulators of the 3D genome.

In this talk, I will present two methods that we have established that significantly expand our understanding of the role of TFs in genome architecture and gene regulation. The first leverages the natural genetic variation and consequent differences in genome architecture between the Castaneous (Cast) and C57BL/6 (B6) mouse strains. Applying a new bioinformatics method built on edgeR to Cast/B6 F1 offspring, we identified genomic regions where 3D architecture differs by strain and by cell type. By examining the strain-specific variants that underlie these differences we can reveal how sequence changes affect TF binding affinity and, in turn, reshape the 3D genome. This has enabled us to validate the genome architectural functions of some TFs, but importantly also implicate many others, not previously thought to facilitate cell-type specific genome architecture.

The second method is DAF-seq, a new deaminase-based long-read sequencing technology that maps protein occupancy along single chromatin fibres. DAF-seq can quantify occupancy heterogeneity in chromatin architecture invisible to previous bulk methods.

Together, these methods investigate the same central question, how DNA sequence encodes epigenetic identity but from complementary angles: natural genetic variation at population scale and direct single molecule observation.

After completing a PhD in experimental physics at La Trobe University, Dr Hannah Coughlan changed fields into bioinformatics and joined WEHI in 2016. Hannah has a joint appointment as a senior postdoc in Professor Gordon Smyth’s lab in the Technology Sciences Division and in Associate Professor Rhys Allan’s lab in the Immunity Division. Her research focuses on the development of methods to understand gene regulation and epigenetics particularly, in the immune system. She recently won the Lorne Genome Mid-Career Award (2026) and the ABACBS Outstanding Mid-Career Research Award (2025).

All welcome!