Profile modifications on histones in gliomas

Epigenetic silencing of tumor suppressor genes plays a causal role in carcinogenesis.

Hypothesis and aims

Epigenetic silencing, the heritable repression of gene expression without DNA sequence alterations, is achieved by two inter-dependent mechanisms: histone modification and DNA methylation. It has recently been discovered that histone modifications can influence DNA methylation and vice versa. Cancer cells are able to use the cellular silencing machinery to turn off expression of tumor suppressor genes. For example, it has been documented that hypermethylation at the promoters of several tumor suppressor genes TSG) such as MGMT, p73 and Rb in oligodendrogliomas and RASSF1A in astrocytomas leads to epigenetic silencing of these genes in early tumorigenesis. However, it is not clear how this aberrant DNA methylation is generated. Because alterations in histone modifications can control DNA methylation, we hypothesize that aberrant DNA methylation in gliomas is caused by histone modification alterations and that these changes can be used as a prognostic marker in brain cancer. With the support of the Brain Tumor SPORE at Mayo Clinic and collaboration with Dr. Jenkins’s laboratory, we have begun to test this hypothesis by profiling modifications on histones in brain tumors.