Despite decades of research on malignant brain tumors in children, an understanding of the fundamental mechanisms of tumorigenesis and the requirements for effective treatment remains inadequate. This proposal addresses the hypothesis that malignant brain tumors in children are caused by abnormalities in chromatin—a complex of DNA and proteins that forms chromosomes. Recent research has shown that mutations in chromatin regulatory proteins or in histone H3—a protein found in chromatin—are common to malignant brain tumors in children. Understanding how the chromatin state (also known as “epigenetics”) regulates tumorigenesis and how it might dictate the therapeutic response is the focus of this proposal.
The aims of this proposal are to test whether:
1. A specific pattern of a chromatin modification called histone H3 lysine 27 tri-methylation
(H3K27me3) is associated with a chromatin signature and gene-expression program characteristic of undifferentiated, therapy-resistant, tumor-initiating cells.
2. Loss of this H3K27me3 pattern induces a chromatin state characteristic of more differentiated, non-clonogenic, and therapeutically vulnerable cells.
By testing whether the balance between H3K27 histone methyltransferase and demethylase activities can determine malignant transformation and the therapeutic response, these studies could shed light on the mechanisms of brain tumorigenesis and lead to the development of novel therapeutics targeting brain tumor epigenetics and histone dysregulation.