The DNA found in a single human cell is approximately 2 metres long. In order to fit into such a small space, the DNA is wound up tightly around many different types of proteins. This combination of DNA and proteins is called chromatin.
Both the DNA and the protein components of chromatin can be “tagged” with a variety of small molecules that affect how the DNA in the tagged region is processed. For example, some tags loosen the grip of the chromatin proteins on the DNA, making the genes in that region more accessible and therefore more likely to be activated. Other tags are recognised by specialised proteins within the cell that attach themselves to the chromatin and alter the activity of nearby genes. These effects can occur regardless of the actual sequence of the DNA in the tagged region; scientists have only quite recently begun to understand how these tags work, and how important they are in the regulation of gene activation. This field of study is called epigenetics.
As with any other complicated control process, tagging mistakes can sometimes occur that alter gene activation and hence cell behaviour. This kind of mistake can lead to the development of cancer, and can potentially be corrected using drugs that target the proteins that add and remove chromatin tags.
We are currently involved in several cancer epigenetics projects, in collaboration with the BC Cancer Agency’s Dr. Keith Humphries (Terry Fox Laboratory), Dr. Gregg Morin (Genome Sciences Centre), Dr. Marco Marra (Genome Sciences Centre), and Dr. Martin Hirst (Genome Sciences Centre):
- EZH2 is a protein that is involved in adding methyl tags to a specific chromatin protein called histone 3. Our group was part of a team that identified mutations in the EZH2 protein in certain kinds of lymphoma. We’ve since found that the mutated version of the protein works together with the normal protein to increase the frequency of methylation of histone 3. Other groups have found evidence that mutation and/or over-activation of EZH2 may also be involved in the development of other types of cancer, including breast and ovarian cancer. We are currently working to understand exactly how mutations in EZH2 are involved in the development of cancer, and we hope that this work will lead to the development of anti-cancer drugs that reduce the activity of the EZH2 protein.
- The MLL5 gene was first discovered in mixed lineage leukemia cells and, like EZH2, it is involved in the methylation of histone 3.We have found that deleting this gene in mice causes defects in the development of sperm and blood cells (including an immune system defect that increases the frequency of eye infections). We have also found that deleting the MLL5 gene makes cells much more sensitive to a drug that is commonly used to treat myelodysplastic syndrome, a condition that often develops into acute myelogenous leukemia. We are currently working to identify the genes that are regulated by MLL5.
- Very recently, new techniques have made it possible to rapidly and efficiently “read” the epigenetic modifications found in a whole genome (the epigenome). We are involved in a collaborative effort, led by our colleagues at the Genome Sciences Centre, to establish a major Canadian centre of epigenome analysis that will deliver complete reference epigenome information on a full spectrum of normal and diseased human cell types, to identify the epigenetic changes that occur as tumours develop.
Recent related papers from the Aparicio Laboratory
- Yap DB, Chu J, Berg T, Schapira M, Cheng SW, Moradian A, Morin RD, Mungall AJ, Meissner B, Boyle M, Marquez VE, Marra MA, Gascoyne RD, Humphries RK, Arrowsmith CH, Morin GB, Aparicio SA. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 2011: 117(8):2451-9
- Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya1 R, Paul JE, Boyle M, Woolcock BW, Kuchenbauer F, Yap D, Humphries RK, Griffith OL, Shah S, Zhu H, Kimbara M, Shashkin P, Charlot JF, Tcherpakov M, Corbett R, Tam A, Varhol R, Smailus D, Moksa M, Zhao Y, Delaney A, Qian H, Birol I, Schein J, Moore R, Holt R, Horsman DE, Connors JM, Jones S, Aparicio S, Hirst M, Gascoyne RD, Marra MA. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 2010 42: 181-185
- Yap DB, Walker DC, Prentice LM, McKinney S, Turashvili G, Mooslehner-Allen K, de Algara TR, Fee J, d’Anglemont de Tassigny X, Colledge WH, Aparicio S. Mll5 Is Required for Normal Spermatogenesis. PLoS ONE 2011: 6(11): e27127
- Heuser M, Yap D, Leung M, Ruiz de Algara T, Tafech A, McKinney S, Dixon J, Thresher R, Colledge B, Carlton M, Humphries RK, Aparicio S. Loss of MLL5 results in pleiotropic hematopoietic defects, reduced neutrophil immune function and extreme sensitivity to DNA demethylation. Blood 2009 113(7):1432-43