Towards a comprehensive biophysical model of gene regulation in dendritic cells

Gene regulation is a multi-step process that plays a central role in shaping the cell response to environmental stimuli. First, pioneer transcription factors (TFs) recognize sequence-specific DNA-binding sites at gene promoters. Then, specific enzymes are recruited which post-translationally modify the histone tails and cause nucleosome remodelling. Additional TFs bind in accessible chromatin regions and ultimately RNA polymerase initiates mRNA synthesis.

An attractive system to model genome-wide regulation of transcription and chromatin dynamics are the dendritic cells (DCs), responsible for the initiation and regulation of immune responses. DCs react to pathogen exposure by triggering regulatory programs that activate or repress thousands of genes during a period of 24h. Recently, exciting new efforts have been able to acquire a vast amount of data improving our understanding of this process. Upon stimulation, time course of ChIP-seq experiments have been able to measure DNA-protein interaction dynamics of 25 TFs and the RNA polymerase II as well as three histone modifications (Garber et al. 2012). Moreover, metabolic labelling of RNA has uncovered basic principles of RNA production and degradation dynamics by measuring over time the accumulation of newly synthesized RNA and the degradation of old RNA (Rabani et al. 2011).

These novel experimental results pose a challenging task: to develop a biophysical model of transcriptional regulation able to integrate all these data in a coherent mathematical framework. The main goal of this PhD project will be to develop a model able to: i) explain the temporal pattern of RNA synthesis from the dynamics of TFs and histone modifications; and, ii) predict the outcome of perturbation experiment through RNAi (Amit et al. 2009).

The ideal candidate should have a strong mathematical background, experience in bioinformatics and good programming skills.

The University of Edinburgh and the SynthSys center offer a unique dynamic and multidisciplinary environment ideal to develop a research career.