Nature's Journal Club

Joe F. Costello

University of California, San Francisco, USA

To an epigeneticist, cancer is encrypted in genes and their packaging.

Early in my career I had the good fortune to study epigenetics in a lab focused on the molecular genetics of cancer. At the time, geneticists typically thought that in cancer, epigenetic changes — which affect regulation of the genome but not the genome’s sequence — were epiphenomena less worthy of study.

This might have made the experience akin to being a Republican mayoral candidate in left-leaning San Francisco; instead it was positively transforming.

As my own research group took shape, I began to integrate genetic and epigenetic theories of malignant transformation. Now, hereditary human cancers and genetically engineered mice once held up as evidence for genetic models also provide evidence for epigenetic models, and we study the interactions of the two mechanisms.

In this light, a recent paper (G. G. Wang et al. Nature Cell Biol. 9, 804–812; 2007) captured my attention because it dissects how one genetic change leads to epigenetic changes that ultimately cause leukaemia.

The work focuses on an abnormal fusion protein — produced after part of one gene fused, or translocated, with part of another — and narrows down its cancer-causing properties to a particular region of the protein. This region mediates an epigenetic change: it adds a methyl group to one amino acid of a histone, part of a gene’s packaging in the nucleus.

The team found that the fusion protein misdirects its methylation to the histones that package HoxA genes, triggering further miscoding of the histones. This activates the genes, which promote self-renewal of blood-cell precursors, contributing to leukaemia.

I wonder if the interactions could be traced back even further. Given the role of epigenetics in stabilizing chromosomes; might it have been epigenetic miscoding that made the gene susceptible to translocation in the first place?


Comments are closed.