CompletedGenetics & Molecular BiologyCells, Biochemistry & Physiology

The chemical biology and function of natural modified DNA bases in genomes

FunderWellcomeCharity-funded
Recipient organisationUniversity of Cambridge
Funding£2.2M
PeriodDec 2018 — Dec 2023

In plain English

AI plain-English summary

Every cell in the human body carries a second layer of chemical instructions written directly onto its DNA, and this project will map how those chemical marks—particularly a modified base called 5-formylcytosine—control which genes are switched on or off. Scientists know that these modified bases help determine whether a cell becomes a neuron, a muscle cell, or something else entirely, but the precise mechanisms remain poorly understood. The researcher will develop new chemical mapping and sequencing tools to track these modifications in mammalian genomes, and will systematically search for entirely unknown DNA base modifications. This is fundamental science: there is no immediate medical application. However, understanding how cells lock in their identity could eventually explain what goes wrong when that identity is lost in diseases such as cancer, where cells revert to a more primitive, uncontrolled state. Past discoveries in this area—such as the role of DNA methylation—have already led to cancer drugs and diagnostic tests. This work could lay the groundwork for similar future breakthroughs.

View original technical description
I aim to elucidate the function of natural, chemically-modified DNA bases in the genomes of model organisms, using chemical biology and physical science approaches on genomic DNA. Modified bases are of fundamental importance to transcriptional programming and cell identity during and after development. The role of the cytosine derivative 5-formylcytosine and its influence on nucleosome formation, active enhancers, transcription and cell identity will be one area of focus to build mechanistic understanding, following on from hypotheses derived from our prior work. There will also be an investigation of 5-carboxycytosine and 5-hydroxymethyluridine and their potential links with transcription regulation. For other modified bases, such as N6-methyladenine, we will develop and use new chemical mapping/sequencing methods to elucidate their function in mammalian systems. The programme will include a systematic discovery of other natural DNA base modifications, building on and augmenting chemical methodologies I have developed to discover and profile modified bases in RNA. The function of newly identified base modifications will be investigated during the programme. The insights provided from these fundamental studies may have far-reaching consequences for normal biology and disease states. Keywords: chemical biology, nucleic acids, DNA, modified bases, epigenetics, sequencing

View the original record at the funder ↗

Researchers

Shankar Balasubramanian (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Original classification

Investigator Award in Science

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.