Research

Structural biology has historically been driven by powerful, albeit low-throughput methods, such as X-ray crystallography or Cryo-electron microscopy. We are developing novel assays that use high-throughput genomic technology, such as next-generation seuqencing, to report on the structures and mechanics of nucleic acids. Subsequently, we train predictive models for the sequence-dependence of DNA mechanics and structure. Our studies continue to reveal a landscape of complex regulatory signals encoded in DNA via the mechanical code.

We are currently developing twist-seq, a methods to measure the sequence-dependence of the torsional rigidity of DNA. We seek to understand how DNA sequence impacts DNA:protein interactions that involve DNA twisting, or impact the mechanics and distributions of DNA supercoils.

Eukaryotic genomes are littered with nucleosomes, which are protein spools around which DNA locally wraps. Covering genomes with nucleosomes serves the critical functions of suppression of abberant transcription and packaging DNA. Nucleosome formation involves extensive DNA bending and twisting. Using genomic and single-molecule methods, we attempt to reveal how the mechanical code of DNA has been used by evolution to encode the location of nucleosomes, guide enzymes that slide nucleosomes, and regulate processes like transcription and replication that require enzymes to locally displace nucleosomes.

Cytosine methylation in the CpG context is a widely prevalant epigenetic modification of DNA. It exercises broad regulatory control over transcriptional processes. We are developing high-throughput methods to characterize how CpG methylation alters the mechanical code itself, and therefore provides cells dynamic control over the physical properties of DNA. In turn, we seek to understand how developmental programmes, or diseases like cancers, that change the epigenetic landscape, could be achieving a part of their downstream effects by contolling DNA mechanics.

Likewise, DNA damage, such as mismatches, are routinely prevalant in all living organisms. We seek to understand how the mechanics of damaged DNA influence DNA repair factors in recognizing and binding to damage sites.

We want to understand how the mechanical and physical properties of DNA make it amenable to supercoiling by topoisomerases such action or transcription. In turn, we want to understand how the mechanical code allows DNA supercoiling to serve as a secondary messenger, communicating environmental conditions to gene expression programmes. We use a combination of high-throughput methods to study DNA mechanics, and single-molecule Rotor Bead Tracking and smFRET to study topoisomerase mechanochemistry.