Dr Aakash Basu

Assistant Professor

ORCID profile

Affiliations
Affiliation
Assistant Professor in the Department of Biosciences

Biography

I began my academic career as a PhD student at Stanford University, USA, working in the group of Zev Bryant. I was fascinated by how biochemical reactions could be visualized one molecule at a time using tools of single-molecule biophysics. I developed magnetic tweezing coupled with Total Internal Reflection Darkfield microscopy to visualize the substeps involved in the transduction of chemical energy in ATP into mechanical work by molecular motors. My particular focus on the motor DNA gyrase - a topoisomerase that supercoils DNA in bacteria - revealed a unique pathway for energy transduction that involves loose coupling between structural transitions in the motor complex and substeps in the ATPase cycle.

By the end of my PhD, I was motivated to apply the tools of single-molecule biophysics to explore biological systems at a scale higher than single molecules. I was awarded a Life Sciences Research Foundation postdoctoral fellowship and joined the group of Jim Hudspeth at The Rockefeller University, USA. Here, I developed a magnetic-tweezing based system capable of interrogating the entire inner-ear tissue. We demonstrated that mechanical tension induced by sound waves on a protein-filament called the tip link is responsible for opening mechanotransduction ion channels on the surface of the inner-ear. In turn, this leads to a downstream nerve response.

At the completion of this project, I wanted to continue applying single-molecule techniques to systems at much higher scales of complexity than single-molecules. I joined the laboratory of Taekjip Ha at Johns Hopkins University, USA as a postdoc to develop single-molecule inspired high-throughput assays to study DNA and chromatin at a genomic scale. Here, I built expertise in using single-molecule Fluorescence Resonance Energy Transfer (smFRET) techniques to study the mechanical-properties of short DNA fragments. smFRET provides very high-resolution measurements, but suffers from extreme low throughout. To overcome this, we developed a genomic assay called “loop-seq” that converts smFRET measurements into a sequencing readout. Sequencing readouts, in turn, can be obtained in very high throughput throughput thanks to the astonishing developments in the field of next-generation high-throughput DNA sequencing techniques. Using loop-seq, we revealed the existence of a ‘mechanical code’ - a mapping between local sequence and the local mechanical properties of the DNA polymer. We showed that evolution has taken advantage of this mechanical code to encode critical regulatory information in the sequence-dependent mechanical and structural properties of DNA.

In 2022, I joined Durham University as an Assistant Professor. I intend to further decipher the mechanical code of the genome and epigenome, understand its regulatory impact on the transcription and metabolism of DNA, and understand how developmental programs and diseases can ‘hack’ the mechanical code to broadly control transcriptional programs. We are developing a combination of novel genomic and single-molecule assays to pursue these goals.

Research Interests

Our lab is interested in achieving the following aims:

1. We want to decipher the mechanical code of the genome and epigenome. In other words, we want to map how the local mechanical properties of DNA vary with local sequence and epigenetic modifications along the entire lengths of the genomes. We will achieve this by developing novel genomic assays that build on the loop-seq technique.

2. We want to understand how mechanical information encoded in DNA regulates transcriptional processes. We will initially focus on understanding how the mechanical profile of DNA along nucleosomes, and epigenetic modifications of the histone octamer, impact transcription through the nucleosomes. We will achieve this via high-throughput in vitro genomic assays, high-resolution single-molecule approaches, and in vivo genome-editing techniques.

3. Our genomic-methods offer the first experimental dynamic measurements of the mechanical and structural properties of DNA on the 10 - 50 bp scale, genome-wide. This provides us with an unprecedented opportunity to develop and train computational models to predict DNA shape, structure, and mechanics, from sequence and epigenetic modifications. Together with progress towards aims 1 and 2, we will use this information to predict mechanically-encoded regulatory information at important genomic loci in various species.

4. We want to understand how chemical and epigenetic alterations to DNA brought about by environmental factors, diseases like cancers, or developmental programs, can achieve a part of their downstream effects by altering the mechanical code.

Publications

Journal Article

Supervision students

Aditi Biswas

Research Postgraduate (PhD)

Full profile

Bailey Forbes