By visualising different proteins expressed within single cells, Scott Berry is setting out to decipher the basic mechanisms that control gene expression.

While our genetic makeup is already encoded in our DNA, the signals are delivered at specific times to individual cells to coordinate which genes are switched on or off, and how actively the genes are expressed – first transcribed to RNA and then translated to protein. The memory of these signals regulating gene expression can be passed on to future generations, all without altering the DNA code. Different stages of biological development or external stimuli can influence gene expression. These changes in turn decide the fate of cells at different developmental stages.

“For example, in stem cell differentiation, a set of genes need to be turned on and off, in a coordinated fashion, to generate the correct cell type. But we don’t really know some of the basic mechanisms underlying this regulation – in particular, how the signals received by a cell are interpreted based on the current state or even the history of that cell,” explains Scott.

Another mystery of gene regulation his team want to understand is how the amounts of RNA – information copied from DNA – are balanced to avoid too much of it accumulating in cells, and what this would mean for the cell if there was.

“There is a basic coupling of RNA degradation and production machinery which allows cells to maintain constant RNA concentration. But how this is achieved is not well understood,” says Scott.

To uncover the mechanisms of gene regulation and RNA homeostasis, Scott’s research team will use a powerful new technology (called 4i) that combines fluorescence protein imaging and computational image analysis. This highly multiplexed protein imaging approach allows them to visualised and measure many different proteins in a large group of cells. The team will be able to quantitatively track which genes are switched on and off at different stages of mammalian development and investigate what factors influence this.

“We can characterise the phenotypes of the cell by measuring up to 50 different proteins in each cell. So, instead of just one at a time, we can now look at the relationships of these proteins to one another. This allows us to study how these relationships vary across cell populations, and how these change in different cellular states or fates,” he says.

“When you look at a population of cells, you’ll find that they are all different. When you take a group of cells and squish them all together in at tube, you can’t see those differences anymore. By imaging them and measuring proteins at the single cell level –  in 10s of 1000s of cells – and using statistical computational approaches to figure out what’s going on in those large populations, you can approach the scale of a biochemical experiment, and with the resolution of a single cell, or even compartments within the cell.”

Returning to Australia from postdoctoral research in Switzerland, Scott is setting up his research group, from October 2021, in the UNSW’s EMBL Australia Node in Single Molecule Science. And he is looking to engage with local researchers working in epigenetics and transcription to dive into problems associated with gene regulation.

“Organisms develop by changing gene expression. This leads to changes in cell fate and structure, which in turn feed-back to regulate gene expression. It’s a fundamental understanding of how cell types are robustly specified by this interplay that help us understand why certain mutations lead to aberrant cell division patterns seen in developmental diseases and cancers,” says Scott.

Learn more about Scott Berry’s research here