Mechanisms of OTX2 Mediated Chromatin Regulation in Medulloblastoma

Background
Medulloblastoma is the most common pediatric brain cancer and is divided into four subgroups with different molecular features and outcomes. There is a pressing need to develop new therapies for these tumors, particularly for Group 3 patients who have the lowest five-year survival. We have recently found that the transcription factor OTX2 is a major regulator of gene activation in Group 3 medulloblastoma and controls many critical genes in this disease. OTX2 operates primarily by binding regulatory DNA elements known as enhancers but its mechanisms of action at these sites are not well understood. 

Project Goal
We now aim to understand these mechanisms by identifying proteins that cooperate with OTX2 and by determining which OTX2 target genes are important for cell growth and survival. We believe that these studies have great potential to reveal genes and pathways that may serve as therapeutic targets for medulloblastoma.

Update - June 2020

Medulloblastoma is the most common pediatric brain cancer and is classified into four subtypes. There is a pressing need to understand the mechanisms that drive these tumors in order to develop new therapies. In particular, the subgroup with the lowest five - year survival (known as Group 3) is poorly understood. We recently used several genomic technologies to study how genes are regulated (either activated or repressed) in Group 3 medulloblastoma tumors. Our studies showed that the transcription factor OTX2 is a major determinant of gene regulation programs in these tumors and is required for the expression of genes involved in the proliferation and survival of medulloblastoma cells. We found that OTX2 primarily binds and activates DNA elements, known as enhancers, but its precise mechanisms of action are yet to be determined. Our work is now focused on elucidating the molecular mechanisms used by OTX2 to activate enhancers in order to identify new potential therapeutic targets for medulloblastoma. While transcription factors themselves are not considered ideal drug targets, they often interact with ‘druggable’ proteins such as chromatin regulators to perform their functions. We have now identified a set of proteins that interact with OTX2 and are currently testing their contributions to OTX2 function in order to determine their potential as new therapeutic targets.