Third party funded individual grant
Acronym: EUReMe
Start date : 01.01.2027
End date : 31.12.2028
DNA methylation is a reversible epigenetic modification of the DNA, where methyl groups are added to specific sites in coding and non-coding regions of the DNA, where a cytosine nucleotide is immediately followed by a guanine nucleotide (so-called CpG sites). DNA methylation is an important regulator of gene expression, and aberrant DNA methylation has been identified as a driving factor in multiple diseases, including cancers (prostate cancer, colorectal cancer, etc.) and neurological disorders such as epilepsy. However, how DNA methylation is itself regulated is largely unknown. Only few effector proteins that add or remove methyl groups at CpG sites are known, which is not sufficient to explain the variability of DNA methylation patterns across biological contexts. EUReMe will address this gap by mapping the uncharted regulatory landscape upstream of DNA methylation, using state-of-the-art machine learning (ML) and computational network biology techniques. Specifically, we aim to discover, characterize, and computationally validate a currently unknown class of “methylation factors” (MFs) that modulate DNA methylation through context-specific DNA binding and interaction with DNA methylation effector proteins, analogously to how transcription factors (TFs) modulate the activity of RNA polymerase II. We will discover putative MFs by adapting ML models originally designed to predict TF activity, will characterize them through annotation of their predicted capabilities to bind to the DNA and to known DNA methylation effector proteins, and will then in silico validate the most plausible candidate MFs via a combination of correlation analyses, natural knockout screens, and in silico perturbation experiments. If successful, EUReMe will thus lay the groundwork for identifying an entirely new functional class of proteins that not only control a key biological process but are also potential therapeutic targets in diseases driven by aberrant DNA methylation.