I really enjoyed your post . I was also wondering if your last question could also pose a question that goes a further step back in the process. Perhaps a previous mutation to some factors controlling chromosome stability/distribution would give origin to that first epigenetic cause that could trigger the fusion of chromosomes leading to the formation of the oncogenic fusion protein. Could it be perhaps a protein affecting the 3D “chromosome territories” in the nucleus?

Thank you for your comment and alternative possible ending. I agree, in addition to speculating on an epigenetic cause of translocation, one also should wonder if the translocation was secondary to another genetic mutation, particularly of a chromosome territory-influencing protein. Did you have one particular protein, or protein family in mind? Perhaps even the hypothetical mutation itself is a result of deamination of an epigenetically modified cytosine, allowing a CpG to TpG change.

I agree that epigenetic change may expose certain genes and/or their regulatory elements to become more easily accessed by mutagens, and genetic mutation may also induce certain epigenetic changes which cause more genetic mutation. In order to prevent genetic mutation, DNA repair system and apoptosis mechanism exist as the barrier to cancer. I am just curious to ask: if epigenetic change is a common cause to cancer, is there any epigenomic repair system, or DNA repair system is already sufficient to stop undesirable epigenetic change by preventing gene mutation? Also, will an epigenetic change triggers apoptosis?

Bill,

Epigenetic changes can induce cell death. For example, the substantial loss of DNA methylation following inhibition of DNA methyltransferase 1 (DNMT1) results in cell cycle arrest and massive cell death in human colon cancer cells (see Nature Genetics 39, 391 - 396 (2007)). In mouse fibroblasts removing DNMT1 results in p53-dependent apoptosis (see Nat Genet. 2001 Jan;27(1):31-9.). The DNA damage response and DNA repair machinery are also critical for epigenetic changes such as DNA demethylation, particularly GADD45A and XPG (see Nature. 2007 Feb 8;445(7128):671-5). I will not be able to comment adequately on potential "repair" systems for epigenetic modifications, but in general the fidelity of reproducing DNA methylation patterns from one cell generation to the next is not as high as DNA sequence fidelity. However, since there are proteins that read epigenetic modifications, and enzymes that reverse specific epigenetic changes, there does seem to be a possibility for "repair".

Has anyone considered a role of epigenetics in triplet repeat expansions?

Joe- Thanks for choosing our paper for journal club and we are all exited. As for your last question, how DNA translocations occur in the first place is still a mystery. In the case of the common leukemia translocation locus MLL/ALL, it has been shown that the usage of topoisomerase II inhibitors dramatically increases the possibility of MLL locus rearrangement in infant leukemias and therapy-related secondary leukemias, suggesting a direct involvement of topoisomerase II in the maintenance of proper chromatin structure (Cancer Res. 1997 Jul 15;57(14):2879-83). But why it affects this locus? A recent paper reports that the known DNA translocation breakpoints share a common pattern in chromatin/histone modifications (Fig 6, Cell. 2007 May 18;129(4):823-37). These histone modification patterns, together with DNA methylation pattern, may create a “open” chromatin structures that are more susceptible to DNA damage agents. Since it is known that chromatin modifications can be actively and selectively added or erased in specific cellular contexts, genetic mutations affecting all these processes and the resulting epigenetic patterns will affect the susceptibility of DNA translocations.

Greg Wang

My interpretation of (Cell. 2007 May 18;129(4):823-37) is that they said not that known translocation breakpoints share a common methylation pattern, but that breakpoints sharing a common methylation pattern tended to be associated with the same diseases.