Cancer research relies on technologies that can interrogate the entire genome, detecting deletions, copy number variants and point mutations responsible for disease. It is becoming increasingly clear that epigenetic lesions in DNA and histone modification are at least as important, and probably more important, than genetic lesions as cells progress towards malignancy, and acquire various attributes, such as drug-resistance. Cancer research at Cold Spring Harbor Laboratory has been at the forefront of this """"""""cancer genomics"""""""" approach, as well as research in epigenetic mechanisms that contribute to these and other diseases. Examples of research topics are summarized in the application, ranging from the role of methylation in breast cancer and chemoresistant AML to replication-induced senescence. Further, we plan to examine epigenomic profiles in model animals and plants, which undergo developmentally programmed changes in epigenetic profiles, and which use RNA interference to guide DNA methylation and histone modification patterns. To do this, we are requesting funds to purchase a Genome Sequencer FLX instrument from Roche Applied Science, which can reliably determine the sequence of the epigenome, even when cytosines are converted to uracil, because longer read lengths permit unambiguous mapping back to the reference genome.
As we learn more about how information is stored in our genome and controls biological processes it has become apparent that in addition to our basic DNA structure, modifications to it, such as the addition of methyl groups in specific places is of crucial importance. Changes in methylated DNA regions can change gene expression in normal development as well as lead to cancer if and possibly other diseases if not properly controlled. We are requesting equipment that will allow us to examine, in great detail and at very large scale, the changes to methylation in the genome so that we can better understand how this process occurs in normal biological processes as well as which genes it regulates in cancer.
