5-hydroxymethylcytosine encodes regulatory information across DNA strands

Speaker: Dr Jack Hardwick, University of Bristol, UK

Abstract:

In mammalian genomes, cytosine modifications encode a layer of regulatory information alongside DNA’s genetic instructions. This information is key to our understanding of health, disease, and ageing. But its distribution in double-stranded DNA has remained unclear.

To address this challenge, we have developed SCoTCH-seq: an accurate and quantitative, base-resolution approach to sequence genomes, together with the two most abundant cytosine modifications—methylation and hydroxymethylation—in both strands of individual DNA fragments. We applied this method to embryonic stem cells and found that at CpG sites, where DNA modifications typically occur, all possible combinations of cytosine can form across the double helix. These ‘CpG states’ have distinct genomic distributions, including key regions such as enhancers and gene bodies, and exhibit different relationships with gene expression.

Overall, our findings indicate that hydroxymethylation and other cytosine variants combine across the DNA double helix to form distinct states of regulatory information.

Bio:

Dr Jack Hardwick is a Lecturer (Assistant Professor) in Biochemistry at the University of Bristol, UK, where his newly established group seeks to elucidate the role of DNA modifications in the brain.

Jack obtained his PhD from the University of Oxford under the guidance of Prof Tom Brown, investigating how chemical modifications to DNA alter its structure and dynamics. Jack then undertook postdoctoral work at the University of Cambridge in the laboratory of Sir Shankar Balasubramanian FRS, where he developed a new method for sequencing cytosine modifications in double-stranded DNA.

Jack’s current work combines sequencing methods development, proteomics, and biophysics to gain new insights into the function of DNA modifications in neurons. Jack has led multiple collaborations between academia and industry, and his work has been recognised by numerous awards, including the Leverhulme Trust Early Career Fellowship and the EPSRC Doctoral Prize.