Research

We use evolution as an experiment.

Most of what we know about chromatin comes from a small number of model organisms. This can make it difficult to distinguish what is fundamentally required to organise a genome from what happens to be conserved in those particular lineages.

Microbial diversity offers a way forward. Across bacteria, archaea and their viruses, evolution has repeatedly invented, replaced and repurposed proteins that interact with DNA. We map these transitions across the tree of life, identify unexpected molecular systems and test their properties experimentally.

Our work centres on three connected research programmes.

1. How do proteins Mimic DNA?

Proteins that interact with DNA must recognise a distinctive molecular surface: an extended, negatively charged polymer with a highly regular geometry. Evolution has repeatedly exploited these recognition rules by producing proteins that resemble DNA.

These DNA-mimicking proteins can occupy DNA-binding surfaces and inhibit the proteins they target. They are particularly important in conflicts between mobile genetic elements and their hosts, where they can disable restriction–modification systems and other cellular defences.

Many DNA mimics are difficult to recognise from their sequences alone. We therefore combine evolutionary analysis with protein structure prediction to search for previously hidden families across microbial and viral genomes. We then test their activity using genetics, biochemistry and structural approaches.

Our central questions are:

How frequently has protein-based DNA mimicry evolved?
Which structural features create an effective mimic?
What determines whether a mimic is highly specific or acts across several targets?
How do mimics and their targets co-evolve?
Can natural DNA mimics provide templates for programmable inhibitors?

Studying these proteins reveals both an underexplored dimension of microbial conflict and the molecular rules by which proteins recognise DNA.

2. How many ways are there to build a chromosome?

Chromosome organisation requires a delicate balance. DNA must be compacted and protected, yet remain accessible to the molecular machinery responsible for gene expression, replication and repair.

Eukaryotic chromosomes are organised around nucleosomes, but microbes reveal a much broader molecular design space. Archaea possess diverse histone systems, some bacteria use histones with unconventional DNA-binding properties, and most bacterial lineages rely on entirely different families of nucleoid-associated proteins.

We investigate:

Which physical and functional properties define a chromatin protein?
Which features of chromosome organisation are universal?
How are established chromatin systems lost, replaced or radically remodelled?
How do reduced or unusual genomes satisfy the minimal requirements of chromosome organisation?
Can proteins from one evolutionary context function in another?

We combine comparative phylogenomics with experiments in both established model organisms and phylogenetically informative microbes. This allows us to move from evolutionary patterns to causal mechanisms.

3. Can we reconstruct and redesign chromatin?

Evolutionary surveys reveal what exists, but experiments are required to understand why particular systems work.

We reconstruct natural and ancestral chromatin systems in tractable organisms, alter their abundance and molecular properties, and measure the consequences for genome organisation and gene expression. These experiments allow us to distinguish proteins that merely bind DNA from proteins capable of functioning as global chromosome organisers.

Ultimately, we want to move from description to design. Can one chromatin system replace another? Can we build orthogonal systems that organise selected regions of a genome? Can molecular mimics be redesigned to target chosen DNA-binding proteins? And can synthetic genomes eventually be paired with synthetic chromatin?

These questions connect evolutionary biology with protein design and synthetic biology. Our long-term aim is to establish general design principles for constructing and controlling chromosome-associated protein systems.

Our approach

Evolutionary discovery

We build phylogenetically balanced genome collections and use comparative genomics, phylogenetics and protein-family analysis to identify unusual systems and repeated evolutionary transitions.

Structure-guided prediction and design

We use protein structure prediction, interaction modelling and computational design to detect relationships that cannot be recognised from sequence alone and to generate experimentally testable hypotheses.

Experimental reconstruction

We use microbial genetics, biochemical reconstitution and quantitative assays to determine what candidate proteins do and how they interact with DNA-associated machinery.

Genome-wide consequences

Proteomics, transcriptomics and genome-wide occupancy measurements allow us to connect molecular mechanism with chromosome organisation, gene expression and cellular fitness.

Our philosophy

We are interested in exceptions because exceptions reveal hidden assumptions. A protein found in an unusual bacterium, a lineage that has lost a supposedly universal chromatin component, or a viral protein with an unexpected structure can expose principles that remain invisible in conventional model systems.

Projects in the lab therefore move deliberately between scales: from evolutionary patterns across thousands of genomes, to molecular interactions between individual proteins, to their consequences for entire chromosomes.