Research

We use structural and cell biology approaches to study the spatial organisation of chromatin and how its dynamic structure underlies organismal development.

The structural dynamics of chromatin

The human genome is hierarchically organized in dynamic assemblies of proteins and DNA, known as chromatin. These assemblies enable robust regulation of gene expression and cell cycle progression. Research in the lab is motivated by the following questions:

  • What are the molecular rules governing chromatin organization?
  • What are the structural elements that determine cell fate and function?

To tackle these questions, we draw on cell biology and cryo-ET combined with focused ion beam (FIB) thinning methods to resolve the molecular detail of specific chromatin regions in differentiating stem cells. 

Through complementary analysis by single-particle cryo-EM, biochemistry and biophysics, we aim to understand how chromatin factors and remodellers associated with these regions give rise to structure and how structure couples to gene activity.

Cryo-FIB, cryo-ET and Cryo-EM images
Cryo-FIB lamella prepared from frozen cells (left); cryo-ET image of the human cell nuclear periphery (center); cryo-EM analysis of chromatin complexes (right)

Structural cell biology technologies

Cryo-FIB/SEM and cryo-ET are versatile tools for exploring the molecular landscape of cells and tissues. However, locating the structure of interest within the cell can be challenging. 

We develop cryo-correlative light and electron microscopy (cryo-CLEM) and labelling strategies to enable robust targeting of cellular processes for visualization and structural analysis.

Questions we are asking include:

  • Can we better utilize fluorescence to localize proteins and genes?
  • What other ways can we analyze spatial cellular data?
Multimodal imaging of a frozen HeLa cell before cryo-FIB milling; and protein labeling in situ for cryo-ET analysis
Cryo-CLEM for targeted FIB lamella preparation (left); in situ protein localization using molecular labels (center, right).