Changes in histone variants, histone modifications, and DNA methylation during cancer progression

In eukaryotes, DNA associates with histone proteins to form a structure known as chromatin, allowing the genome to be tightly packaged into the nucleus. The basic repeating unit of this structure is the nucleosome, approximately 146 bp of DNA wound around an octamer of histone proteins. Because nucleosomes can present a barrier to active chromatin processes, such as transcription, mechanisms to modulate the stability and location of nucleosomes have evolved. One mechanism to alter the properties of the nucleosome is the incorporation of histone variants. For example, there is evidence that the incorporation of H2A.Z and H3.3 into the same nucleosome results in a very unstable structure, and this instability may allow Pol II to better initiate transcription (Jin et al. 2009). Another component of epigenetic information is the covalent modification of DNA itself. DNA methylation may impact gene expression by directly preventing transcription factors from binding to their target sequences, or indirectly by influencing the properties of surrounding nucleosomes. In my thesis work, I examined global changes in histone modifications, histone variants, and DNA methylation in several mouse cancer models to ask how epigenetic information is altered in cancer cells. In the course of this work, we found H2A.Z and DNA methylation were anti-correlated in mammalian cells, and that during lymphomagenesis, dramatic changes in H2A.Z genome localization were mirrored by opposite changes in DNA methylation. This suggests a mechanism by which aberrant DNA methylation can invade promoters during tumorigenesis, allowing tumor suppressor genes to be aberrantly silenced. In addition, we observed large changes in the dynamic structure of chromatin in lymphoma cells, as well as changes in histone H3 variant abundance and H3 modification levels in liver cancer. Finally, we identified two genes, Zikl and Gja9, consistently methylated in colon cancer, suggesting these genes may be tumor suppressors (Borinstein 2010). Taken together, these projects suggest that dramatic changes in chromatin composition on a global level, as well as aberrant changes in epigenetic regulation of specific loci, are important features of cancer and may provide useful prospects for early detection, prognostic, and treatment methods.