Interview: Epigenetic patterns in a complete human genome

Ariel Gershman is a PhD candidate in Winston Timp’s lab at Johns Hopkins University, where she focuses primarily on sequencing technology, genome assembly and epigenetics, working closely with the Telomere-to-Telomere (T2T) Consortium to use nanopore sequencing to generate a complete map of the human methylome. We caught up with Ariel to talk about her work with the T2T Consortium, the challenges of studying highly repetitive regions, and how nanopore sequencing is changing the study of epigenetics.

In addition to Ariel's interview, you can also find out more about her research by watching a webinar she recently presented on ‘Epigenetic patterns in a complete human genome'.

Watch webinar

What are your current research interests?

My research interests include utilizing long-read methods to assemble and annotate the genomes of non-model organisms, and to understand the epigenetic regulation of repetitive regions of the genome and their role in genome function and genome integrity.

What first ignited your interest in genetics and epigenetics?

I first became interested in genetics as an undergraduate, working on understanding amphibian immunity to fungal disease. This interest was further ignited when I had the opportunity to work with the T2T group on the first complete assembly of chromosome X. I had a very minor role of looking at CpG methylation patterns across the new regions of the chromosome X assembly — the results of the analysis revealed an unexpected pattern that the group later determined to have a large functional role in identity of the centromere. Since the chromosome X work, I have worked on many other projects within the T2T Consortium, every time advancing my knowledge and getting to see revolutionizing science happen in real time. It has been an incredible honor to learn from this group of scientists, and their drive to advance human genetics is infectious and has motivated me to become even more excited about the research and the direction of the field in the future.

How is nanopore sequencing changing the study of epigenetics? How has it benefitted your work?

Unlike sequencing-by-synthesis strategies, nanopore sequencing directly probes the DNA, allowing for simultaneous measurement of the base sequence and epigenetic state, with long, direct reads providing deeper insights into the epigenetic patterns on individual molecules. The single-read nature of nanopore sequencing also provides further insights into the epigenetic cell-to-cell heterogeneity. With the combination of massive improvements to complete genome assemblies and the mappability of ultra-long nanopore reads, it’s even possible to investigate epigenetic regulation in the largely overlooked satellite arrays that other methods cannot accurately probe.

What impact could a complete interrogation of the human epigenome have on our understanding of epigenetic regulation and human biology?

A significant portion of CpGs in the genome are in highly repetitive regions that are difficult to probe, and their epigenetic dysregulation can result in cancer, irregular transcription of regulatory RNAs, and improper chromosome segregation. Having a complete human reference genome allows us to study these regions that have been previously left out of genetic and epigenetic analyses.

What have been the main challenges in your work and how have you approached them?

The repetitive regions of the genome that we probed in our work are challenging for assembly and mapping. To combat these challenges, we relied on the assemblies from the T2T Consortium and novel mapping techniques and pipelines generated from those within the Consortium. On our end, we strove to generate ultra-long nanopore sequencing reads to aid in mapping across large repeat arrays.

What’s next for your research?

As the Human Pangenome Reference Consortium (HPRC) and T2T Consortium generate more high-quality reference assemblies of diverse individuals, we hope to further understand the variability of epigenetic regulation between humans, and between different alleles within the same individual. Additionally, our work highlights the potential of long-read epigenetic methods to fully access the epigenetic landscape of repetitive regions of the genome. We are also interested in adapting other sequencing techniques to utilize long reads, revealing more complex patterns of genome regulation, by adding to and building off the newly growing repertoire of long-read methods, such as NanoNOMe, Fiber-seq, DiMeLo-seq, and Pore-C.