Research

Epigenetics and Modified Bases

We are interested in understanding chemical modifications to DNA and the effect of such changes to the structure and function of DNA. DNA is made up of four bases – cytosine, guanine, adenine and thymine. However, these bases can naturally undergo chemical modification leading to new bases. Changing one of the bases in a strand of DNA in this way alters its property and function by controlling how the sequence is interpreted. This can affect how genes are switched on and off in different cell types, tissues and organs.

The modified base 5-methylcytosine (5mC) is well-known epigenetic mark that can regulate transcription of the genome. Since 2009 three further modified bases have been detected in the mammalian genome. These are the TET-enzyme generated bases; 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). The presence of these modifications opens up questions as to their function in normal cellular biology and disease states.

 

We are developing chemical tools and genomic methods to map and elucidate the function of these modified bases.  We are also exploring the molecular basis for their involvement in biological mechanisms.  Part of this work exploits state of the art genomics technologies. We have already created methods to quantitatively sequence 5mC, 5hmC and 5fC at single-base resolution. Such tools allow much more accurate study of these epigenetic marks.

The scope of our work will also include the identification, mapping and elucidation of the biological function of other base modifications in the DNA and RNA of various organisms.

References

An Upstream G-Quadruplex DNA Structure Can Stimulate Gene Transcription

Y Chen, A Simeone, L Melidis, S Martinez Cuesta, D Tannahill and S Balasubramanian
ACS Chem. Bill., 2024, early online publication
DOI: 10.1021/acschembio.3c00775

G-quadruplex DNA structure is a positive regulator of MYC transcription

I Esain-Garcia, A Kirchner, L Melidis, R de Cesaris Araujo Tavares, S Dhir, A Simeone, Z Yu, S K Madden, R Hermann, D Tannahill and S Balasubramanian
PNAS, 2024, 12 (7), e2320240121
DOI: 10.1073/pnas.2320240121

Unrepaired base excision repair intermediates in template DNA strands trigger replication fork collapse and PARP inhibitor sensitivity

A Serrano-Benitez, S E Wells, L Drummond-Clarke, L C Russo, J C Thomas, G A Leal, M A Farrow, J M Edgerton, S Balasubramanian, M Yang, C Frezza, A Gautam, J Brazina, K Burdova, N C Hoch, S P Jackson and K W Caldecott
The EMBO Journal., 2023, e113190
DOI: 10.15252/embj.2022223190

A Photoredox Reaction for the Selective Modification of 5-Carboxycytosine in DNA

B J Mortishire-Smith, S M Becker, A Simeone, L Melidis and S Balasubramanian
J. Am. Chem. Soc., 2023, early online article
DOI: 10.1021/jacs.2c12558

Selective Functionalisation of 5-Methylcytosine by Organic Photoredox Catalysis

M M Simpson, C C Lam, J M Goodman and S Balasubramanian
Angew. Chemie, 2023, e202304756
DOI: 10.1002/anie.202304756

Simultaneous sequencing of genetic and epigenetic bases in DNA

J Füllgrabe, W S Gosal, P Creed, S Liu, C K Lumby, D J Morley, T W B Ost, A J Vilella, S Yu, H Bignell, P Burns, T Charlesworth, B Fu, H Fordham, N J Harding, O Gandelman, P Golder, C Hodgson, M Li, M Lila, Y Liu, J Mason, J Mellad, J M Monahan, O Nentwich, A Palmer, M Steward, M Taipale, A Vandomme, R S San-Bento, A Singhal, J Vivian, N Wójtowicz, N Williams, N J Walker, N C H Wong, G N Yalloway, J D Holbrook and S Balasubramanian
Nature Biotechnology, 2023, early online article
DOI: 10.1038/s41587-022-01652-0