Epigenetics of cancer progression: I view cancer as a disease of epigenetic plasticity involving “three M’s": epigenetic Modulators that activate or repress the epigenetic machinery; epigenetic Modifiers that are the epigenetic machinery and are commonly mutated in cancer; and epigenetic Mediators that are the gene targets of the modifiers, define the epigenetic landscape, and drive cancer plasticity. Our laboratory’s main focus recently has been on pancreatic ductal adenocarcinoma (PDAC). Earlier, we found that human PDAC metastases arise through epigenetic change in the absence of additional new driver mutations. We recently have found through a CRISPR screen that KLF5 is a modulator of this process, acting on several epigenetic modifiers including MTHFD1 and NCAPD2, which in turn modify the chromatin landscape at epigenetic mediator genes controlling proliferation, metastasis, and enhancer reprogramming. We are continuing to use animal models and relate them to human cancer to understand the mechanism and consequences of epigenetic plasticity in PDAC progression. We are also applying mathematical tools to understand epigenetic plasticity in terms of DNA methylation entropy, and relating entropy to transcription factor binding sites driving variable gene expression in cancer and development.
Engineering epigenetic resilience: Individual health and resilience to stress is shaped by the interaction of genes and the environment. The epigenome provides the molecular interface through which environmental and developmental factors shape gene regulation. To better understand this interaction at the molecular level, we and our collaborators have developed a genome-wide allele-specific methylation framework using long-read sequencing to characterize intergenerational epigenetic inheritance in mice. This framework revealed non-Mendelian inheritance, including emergent epialleles, imprinting events and paramutation, in a non-transgenic mammalian genome. This work identifies parts of the genome that are potentially malleable, and also demonstrates emergent methylation patterns that could lead to new phenotypes. We are modifying the epigenetic machinery in in a targeted way through pharmacological, dietary, or genetic intervention, in order to reverse epigenetic memory and improve resilience to stress. We are also adapting these tools to human population studies to fill in gaps in the missing heritability of common human disease.
