During normal replication of the chromosomes, DNA and epigenetic modifications in DNA and histones are copied to daughter cells and this process is vital for maintaining cell identity and proper cell function. Although we have good models for how cells co py DNA methylations, the exact mechanisms of how histone modifications are transferred from one cell generation to the next remain elusive. Consequently, today this process cannot be manipulated for targeted epigenetic reprogramming. In Epi++, I aim to d evelop a method that manipulates the process of epigenetic inheritance between human mother and daughter cells to reprogram the cells' epigenetic state. Central to this method will be a computational model that identifies non-coding RNAs (ncRNAs) that are essential in maintaining histone modifications and that predicts the regulatory targets of these "anchor RNAs". To develop the computational model, we will use a multi-disciplinary approach that combines high throughput genomics in replicating cells, bio informatics, machine learning, and RNA interference to identify, characterize, and validate such anchor RNAs. By addressing one of the important open questions in epigenetics: "how are histone modifications maintained during DNA replication?" Epi++ will open new, major research possibilities in at least three separate areas. First, the computational model can be used to assign potential functions and thereby guide future experiments on the plethora of recently identified ncRNAs. Second, the model will en able future research on genetic variation that affect epigenetic inheritance and thereby cause disease. Third, the model will set the trend for programmable epigenetics as tool within mammalian biotechnology and human therapeutics. In summary, Epi++ will likely have a high impact on future epigenetics research.
Project leader: Pål Sætrom
Institution: Institutt for datateknologi og informatikk