Sox transcription factors: balancing pancreatic development and dysfunction in cancer

The project seeks to better understand these mechanisms at the biochemical and cellular levels and understand their roles in both diabetes and cancer. Specific Aim 1: To understand the mechanism by which Sox9 selectively drives pancreatic developmental programs and dysregulation in cancer. We will do detailed biochemical analysis of the modification of Sox9 by cofactors which leads to dimerization. Detailed analysis including titration of Sox9 with cofactors as well as controlled dimerization will be performed. We will additionally also look at the genomic landscape of Sox9 binding to better understand its effects on the pancreatic program using iPSC derived beta cells. Specific Aim 2: To understand the mechanism by which Sox17 selectively drives the endodermal program and dysregulation in cancer. The genomic landscape of Sox2 (double mutant which converts Sox2 to Sox17) will be performed using a CRISPRed cell line. The CRISPRed line is currently being constructed by Thermofisher (current grant). This cell line will be used to interrogate both the endodermal specific programs as well as pathways leading to carcinogenesis. The resulting genomic information will be used to choose specific enhancers being bound by the mutant Sox17 and to identify potential partners. The combination of biochemistry and cellular biology will help find detailed mechanisms of Sox TFs driving pancreatic differentiation and carcinogenesis.

Hamad Bin Khalifa University (HBKU)