ESR Project 12: Regulation of Trib and identification of transcription factors targeted by Trib1/3
Miriam Ruiz Cantos
The Tribbles (TRIB) pseudokinases evolved from a common ancestor (a TRIB2 homolog) and comprise three different evolved genes, TRIB1, TRIB2 and TRIB3, which have both unique and shared features and activities. Individually and together they contribute to the control of multiple aspects of eukaryotic cell biology, such as regulation of cell cycle, differentiation, metabolism and response to cell stress. These pseudokinases have been attributed two main mechanisms of action: first, recruiting protein substrates for ubiquitination (Figure 1) and second, integration and modulation of signals flowing into and through MAPK and AKT pathways.
Figure 1. Ribbon Representation of human Tribbles 1, which comprises 372 amino acids. No structure has been resolved between residues 342 and 357, where the transcription factor C/EBPα is predicted to bind (James M. Murphy et al., 2015). C/EBPα and TRIB1 participate in a regulatory feedback loop where C/EBPα promotes TRIB1 transcription, and the E3 ubiquitin-protein ligase COP1 ubiquitinates C/EBPα for degradation (Robert C. Bauer et al., 2014).
It is envisaged that adequate controls of TRIB transcription is both complex and essential for maintaining cell cycle, cell integrity and lipid metabolism. My project, therefore, will focus on elucidating what regulates TRIB1 (and ultimately TRIB3) transcription, looking into transcription factors, adjacent non-coding sequences and changes in histone modifications and chromatin looping during different stages of cell differentiation. Currently, my studies are collating the vast amount of data residing in genomic databases, which will then be used to design experiments to understand the epigenomic processes regulating TRIB1 transcription in those cell types pertinent to the TRAIN program.