Understanding the functional relationship between c-Myc and PADI4 in cancer and tissue regeneration

Main strategic BBSRC theme: Understanding the rules of life

The aim of this project will be to investigate the functional relationship between the transcription factor c-Myc and the post-translational modification catalyzing enzyme peptidylarginine deiminase IV (PADI4, PAD4), in the contexts of tissue regeneration and cancer biology.

c-Myc is a pleiotropic transcription factor and proto-oncogene and its deregulation is associated with poor cancer prognosis. Additionally, c-Myc is one of the Yamanaka factors that can drive reprogramming of somatic cells to a pluripotent state, and has been associated with positive outcomes of tissue regeneration.

The Christophorou lab have identified a role for PADI4 in cell reprogramming and tissue regeneration and current data suggest that these functions are mediated through histone citrullination and modulation of chromatin functions. Unpublished data from the lab demonstrate that, in the context of cell reprogramming, c-Myc is necessary and sufficient for the induction of PADI4 expression and activity.

In this context, the PADI4-activating cells undergo a form of cell death akin to Neutrophil Extracellular Trap (NET) formation, releasing their chromatin, to the extracellular space, where it is sensed as a damage-associated molecular pattern (DAMP) and modulates the state and function of neighbouring cells through activation of innate immune signalling pathways (Grinat et al, In preparation).

The specific aims of the project are: 1) Define the mechanism through which c-Myc leads to PADI4 induction. 2) Understand the consequences of Myc-driven PADI4 activation in stem cells and cancer cells. 3) Investigation of Myc-driven PADI4 activation during tissue regeneration. Key methods: - Cell culture

- Genetic modification - Western Blottting and Immunoprecipitation - Genomic profiling - Histology, immunohistochemistry - Bioinformatics References: 1. Christophorou et al., Nature, 2014; doi: 10.1038/nature12942. 2. Murphy et al., Cancer Cell, 2009; doi: 10.1016/j.ccr.2008.10.018. 3. Bywater et al., Nat Comms, 2020; doi: 10.1038/s41467-020-15552-x.

Keywords: Peptidylarginine deiminase IV (PADI4, PAD4), histone citrullination, c-Myc, transcriptional regulation, extracellular chromatin, cancer, tissue regeneration