Developing new systems to uncover how transcription factors activate their target genes

How transcription factors activate their target genes remains poorly understood. We have developed a screening system to create a map of the proteins required for activation by a series of transcription factors, providing the first unbiased and comprehensive picture into the specificity and heterogeneity of gene activation.

CHARLES BELL
Post-doctoral Researcher 
Cancer Epigenetics Lab, Peter Mac and UMCCR 

Complex organisms are composed of a myriad of distinct cell type that are all ultimately encoded in a single genome. To produce this range of cell types it is therefore necessary to turn on or off genes at different times and in different combinations. Therefore, it is these gene expression programs that ultimately define a cells identity. This process is coordinated by a class of proteins called transcription factors, which have the unique ability to directly read the genetic code. Upon recognising their targets, transcription factors must then communicate a specific regulatory message to the target genes to ensure that the gene is appropriately regulated. How transcription factors recognise their target genes is now relatively well understood, however how they actually communicate their regulatory information to their targets and the nature of this information remains poorly characterised.

Here, we have developed a screening system to provide unbiased and comprehensive insights into how transcription factors activate their target genes. This system provides us with the first glimpse into the logic of this process, revealing unexpected diversity in the mechanisms of gene activation. These findings provide new insights into this fundamental aspect of biology and will help to prioritise the development of next generation epigenetic therapies, by focussing efforts onto transcriptional proteins with more specific functions.

Dr Charles Bell is a post-doctoral researcher studying the fundamentals of transcriptional regulation and their relevance to development and disease. After completing his degree at the University of Queensland, Charles trained for 3 years as a research assistant in the laboratory of Professor Andrew Perkins. There, he studied a transcription factor and its associated long non-coding RNA involved in regulating mouse gastrulation. Charles then moved to Melbourne to perform a PhD with Professor Mark Dawson, where he investigated how cancer cells reprogram their epigenetic state in order to resist targeted therapies. After publishing the major manuscript of his PhD, Charles then transitioned back to his core interest in transcriptional regulation, developing a completely new and innovative screening system, with the goal of understanding how transcription factors activate their target genes. Charles hopes that by expanding the use of these reductionistic systems, we can build from the bottom up to dissect the rules of transcriptional regulation and eventually understand how transcription is integrated with other processes in the cell.