Completed Genetics & Molecular Biology Cells, Biochemistry & Physiology

The Chemical Biology of the Genome and the Epigenome.

Funder Wellcome Charity-funded
Recipient organisation University of Cambridge
Funding £1.7M
Period Nov 2012 — Nov 2018

In plain English

AI plain-English summary

The human genome contains a hidden layer of chemical marks on DNA that help control which genes are switched on or off, and this project will map and decode several newly discovered ones. Most people know DNA as a simple four-letter code—A, C, G, and T—but cells add chemical tags to these letters to fine-tune gene activity. This "epigenetic" layer is crucial for normal development and goes wrong in diseases like cancer. Until recently, scientists knew of only one such modified base (5-methylcytosine). In the last decade, Shankar Balasubramanian’s team discovered three more—5hmC, 5fC, and 5caC—and suspect dozens of others exist. Their functions remain largely unknown. This research will develop new chemical tools to sequence these modified bases across the entire genome, then ask two fundamental questions: what roles do these marks play in health and disease, and how many different modified bases actually exist in mammalian DNA? This is fundamental science. It will not produce a drug or diagnostic tomorrow. But understanding the full epigenetic alphabet could eventually reveal new targets for cancer therapies, explain why some genes misfire in developmental disorders, and rewrite textbooks on how genomes work—much as the discovery of DNA methylation itself did decades ago.

View original technical description
Molecular medicine and biology in the 21st century are being transformed by our understanding of the genome. This has been facilitated by a revolution in analytical technologies, that include our invention of Solexa-Illumina sequencing. However, this is just the beginning. Other properties of nucleic acids are of vital importance to our understanding of life and disease. My research exploits chemical biology to understand the structure, chemistry and function of DNA. My broad goal is to comp rehend the importance of chemical modification of DNA bases to biology and disease. This will include the recently discovered bases 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxymethylcytosine (5caC) as part of a wider, rigorous and systematic exploration of the 100 or so other modified bases purported to exist in nature. To achieve this I will develop and exploit new chemical/analytical approaches for studying alternative bases in the genome. My approaches will follow di rectly from our very recent inventions of quantitative sequencing of 5hmC at single base resolution and the genome-wide chemical mapping of 5fC. There are two main questions I will address: A. What are the (epi)genetic roles of 5hmC, 5fC and 5caC in normal biology and disease? B. How large is the (epi)genetic alphabet in mammalian DNA?

View the original record at the funder ↗

Researchers

Shankar Balasubramanian (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

The chemical biology and function of natural modified DNA bases in genomes
The Structure, Chemistry and Function of the Genome
Chemical assisted enrichment of 5-carboxycytosine that also allows for DNA sequencing at single base resolution.
Chemical Strategies for Epigenome Wide Discrimination of 5-Hydroxymethylcytosine and 5-Methylcytosine
Sequencing of Epigenetic Marks

Original classification

Investigator Award in Science

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