Dr Martin Higgs

Supervisor Details

Contact Details

Institute of Cancer and Genomic Sciences, University of Birmingham

Scientific Background

Research Interests

Martin’s current research focuses around identifying how cells respond to and resolve DNA damage, particularly that arising during DNA replication.

He is particularly interested in elucidating how protein Lysine methylation contributes to safeguarding genome stability, and in identifying novel factors involved in this response. He is also interested in elucidating how deficiencies in these pathways contribute to human disease.

He also maintains a long-standing interest in the impact of chronic viral infection on this process, and on the consequences of this on the DNA damage response during carcinogenesis.

For more details, please visit his lab page.

Current Projects

Assessing the impact of histone methylation on DNA repair and anti-cancer therapies.
Investigating the role of lysine methyltransferases in maintaining genome stability.
Uncovering new roles for non-histone methylation in DNA repair and replication.
Profiling mutations in the lysine methylation apparatus and the impact on genomic stability.
Investigating how genome instability contributes to rare diseases caused by mutations in lysine methyltransferases.

Research Groups

Institute of Cancer and Genomic Sciences

Lysine Methylation and DNA Damage Group

Centre for Neurogenetics

Birmingham Centre for Genome Biology

Centre for Rare Disease Studies (CRDS) Birmingham

Supervision Style

In three words or phrases: Supportive, organised, committed.

Provision of Training

Myself and my experienced post-docs/PhD students will provide your technical training at the beginning of your PhD, leading to more independence later. In the latter stages of your studies you will be expected to independently troubleshoot methodology when appropriate.

Progression Monitoring and Management

I will be available for troubleshooting and guidance on a daily/weekly basis throughout your PhD but expect you to take full ownership of your project as your progress. During weekly meetings we will set goals and expectations together that will allow you to achieve your full potential.

Communication

My lab communicates by email and WhatsApp during the weeks and occasionally at weekends. I do not require an instant response and expect you to manage your work/life balance yourself. I am happy to discuss any issues that are impacting your ability to fulfil your potential or my expectations.

PhD Students can expect scheduled meetings with me:

In a group meeting

At least once per week

In year 1 of PhD study

At least once per week

In year 2 of PhD study

At least once per week

In year 3 of PhD study

At least once per fortnight

The meetings will be face to face and I am usually contactable for an instant response (if required) on every working day.

Working Pattern

Work in my lab requires being present in the laboratory during the core hours of 9am-5pm Monday-Friday.

Notice Period for Feedback

I need at least 2 week’s notice to provide feedback on written work of up to 5000 words.

MIBTP Project Details

Current Projects (2025-26)

Studying how epigenetics controls DNA repair in neuronal cells

See the PhD Opportunities section to see if this project is currently open for applications via MIBTP.

Please Note: The main page lists projects via BBSRC Research Theme(s) quoted and then relevant Topic(s).

Studying how epigenetics controls DNA repair in neuronal cells

Secondary Supervisor(s): Professor Timothy Barrett

University of Registration: University of Birmingham

BBSRC Research Themes: Understanding the Rules of Life (Neuroscience and Behaviour)

Project Outline

Our DNA is under constant attack from a variety of DNA damaging agents, which pose a significant threat to development, neurological function, and organismal survival. To counteract this, cells have evolved complex DNA damage response (DDR) pathways which repairs this damage. A critical part of these pathways is the control of repair proteins by post-translational modifications. My group is interested in one DDR-associated PTM, lysine methylation, and the ‘lysine methyltransferase’ enzymes that catalyse this. Our focus is to understand how these enzymes control DNA repair.

Studies from my lab have demonstrated that one particular lysine methyltransferase is required to repair several types of DNA lesions (1-2). Interestingly, patients harbouring mutations in this enzyme and related methyltransferases exhibit neurological and neurodevelopmental defects (3-4), and also have elevated levels of DNA damage. Since this family of methyltransferases are known to target histone H3, this suggests that neuronal function relies on DNA repair controlled by histone methylation.

Aims and experimental approaches: The aim of this studentship is therefore to characterise how lysine methylation of histone H3 controls DNA repair in neurons.

The project has 3 main objectives:

1) Establish neuronal models lacking these enzymes: We will first use CRISPR/Cas9 to delete these lysine methyltransferases from existing iPSC/hESC cells or from immortalised neuronal SH-SY5Y cells. In parallel, we will clone existing wild-type, catalytic-deficient or transcriptionally-incompetent methyltransferase variants into viral vectors and use these to create complemented iPSCs. We will then verify the localisation and expression of these variants and derive these iPSC cells into neurons for following experiments.

2) Uncover how histone lysine methylation repairs DNA damage in neurons: Using these cellular systems, we will investigate the role of histone lysine methylation in expression of neuronal cell markers, as well as neuronal growth, survival, and rates of apoptosis. We will next investigate how histone methylation contributes to the repair of DNA double strand breaks and oxidative DNA damage in these cells using immunofluorescence for known DNA damage markers, as well as immunoblotting and comet assays.

3) Investigate the impact of inhibiting histone demethylation on neuronal DNA repair and fitness: Lysine demethylases (KDMs) counteract methyltransferases and remove methyl marks from histones. Our preliminary data in somatic cells suggest that pharmacological inhibition of these KDMs to restore histone H3 methylation reinstates DNA repair function. We will therefore investigate how different KDM inhibitors (reversible/irreversible, catalytic vs allosteric) affect neuronal fitness and DNA repair, basing our assays on data from aim 2. We will also investigate the impact of transcription on this process and investigate the roles of any common differentially expressed genes in DNA repair.

This PhD project will offer extensive training opportunities in a variety of integrated genomics techniques, generate novel data on how lysine methylation regulates the DNA damage response in neurons, and lead to a greater understanding of the control of neuronal DNA repair.

References

1) Higgs et al., 2018. Histone methylation by SETD1A protects nascent DNA through the nucleosome chaperone activity of FANCD2. Molecular Cell; 71(1): 25-41.

2) Bayley et al. 2022H3K4 methylation by SETD1A/BOD1L facilitates RIF1-dependent NHEJ. Mol Cell. 82:1924-1939. doi: 10.1016/j.molcel.2022.03.030

3) Kummeling et al., 2021.Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome. Molecular Psychiatry. 26(6):2013-2024. doi: 10.1038/s41380-020-0725-5.

4) Fallah et al., 2021. Impaired Regulation of Histone Methylation and Acetylation Underlies Specific Neurodevelopmental Disorders. Front Genet. 11:613098. doi: 10.3389/fgen.