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.

 

epigenetics

 

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:

5-Formylcytosine can be a stable DNA modification in mammals
M Bachman, S Uribe-Lwis, X Yang, H E Burgess, M Iurlaro, W Reik and S Balasubramanian
Nature Chemical Biology, 2015, 11, 555–557
DOI: 10.1038/nchembio.1848
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Selective Chemical Labeling of Natural T Modifications in DNA
R E Hardisty, F Kawasaki, A B Sahakyan and S Balasubramanian
J. Am. Chem. Soc.2015137 (29), 9270-9272
DOI: 10.1021/jacs.5b03730
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5-Formylcytosine alters the structure of the DNA double helix
E Raiber, P Murat, D Y Chirgadze, D Beraldi, B F Luisi and S Balasubramanian
Nature Structural & Molecular Biology2015, 22, 44–49
DOI: 10.1038/nsmb.2936
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5-Hydroxymethylcytosine is a predominantly stable DNA modification
M Bachman, S Uribe-Lewis, X Yang, M Williams, A Murrell and S Balasubramanian
Nature Chemistry20146, 1049-1055
 DOI: 10.1038/nchem.2064
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Quantitative sequencing of 5-formylcytosine in DNA at single-base resolution
M J Booth; G Marsico; M Bachman; D Beraldi; S Balasubramanian
Nature Chemistry, 2014, 6, 435–440
DOI:10.1038/nchem.1893
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A screen for hydroxymethylcytosine and formylcytosine binding proteins suggests functions in transcription and chromatin regulation
M Iurlaro; G Ficz; D Oxley; E Raiber; M Bachman; M J Booth; S Andrews; S Balasubramanian; W Reik
Genome Biology, 2013, 14, R119
DOI:10.1186/gb-2013-14-10-r119
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Genome-wide distribution of 5-formylcytosine in embryonic stem cells is associated with transcription and depends on thymine DNA glycosylase
E Raiber; D Beraldi; G Ficz; H Burgess; M R Branco; P Murat; D Oxley; M J Booth; W Reik; S Balasubramanian
Genome Biology, 2012, 13, R69
DOI: 10.1186/gb-2012-13-8-r69
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Quantitative Sequencing of 5-Methylcytosine and 5-Hydroxymethylcytosine at Single-Base Resolution
M J Booth; M R Branco; G Ficz; D Oxley; F Krueger; W Reik; S Balasubramanian
Science, 2012, 336, 934-7
DOI: 10.1126/science.1220671
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