Varying the Terrain of Epigenetic Landscapes: Implications for Human Cancer

The journey from embryonic stem cell to a fully developed liver, heart or muscle cell requires not only having the right set of genes, but also having genes that are turned on and off at the right time — a job that is handled in part by DNA‐packaging proteins known as histones. Cells use a number of mechanisms to establish and maintain the activation or silencing of specific genes. Among these is the chemical modification of histones, discussed in the second lecture. In addition, histone variants, which differ from other histone proteins by just a handful of amino acids, can be inserted at specific locations in the genome to provide a cell with another mechanism for fine‐tuning gene regulation. Dr. Allis' group has shown that histone variants play an important role in determining how and when genes are read or are silenced. Recent work from Dr. Allis' laboratory has focused upon one member of the histone H3 family known as H3.3. In comparing the genome‐wide localization of H3.3, Allis and co‐workers found that histone H3.3 is prevalent in regions of the genome where active genes are found, as well as in silent regions, such as at the ends of chromosomes, called telomeres. They went on to identify several additional proteins associated with H3.3. Two of them, ATRX and Daxx, were then discovered to be frequently mutated in a sporadic, non‐functional pancreatic cancers, known as panNETs. Current experiments seek to determine whether genetic deficiency of Daxx and ATRX in pancreatic neuroendocrine cells is sufficient to induce tumorigenesis. Mutations in histone H3.3 itself have also been found in pediatric brain tumors (gliomas). Allis and co‐workers have recently asked ‐‐ how one of these mutations might act cause cancer in young children‾ Surprisingly they find that a specific mutation in H3.3 often found in the pediatric brain tumors inhibits histone methylation of all histone H3 at this site, a site methylated to induce gene silencing. Moreover, the specific mutation in H3.3 acts by inhibiting the enzyme responsible for bringing about methylation at this site. These data indicate that this specific type of mutation in histones might be more broadly applicable to the development and progression of other tumour types. It is not yet clear why aberrant epigenetic silencing of this enzyme results in the development of pediatric brain tumors, and further research is needed in an attempt to develop a better understanding of these difficult to treat childhood cancers.