Gen-Epics – an ERC funded research project

Our laboratory has a long-standing interest in studying epigenetic influences on gene activity, predominantly via our work on DNA methylation and CpG islands. This ERC grant will explore the possibility that the genomic sequence itself is a major contributor to epigenetic conditioning that sets up gene expression programmes. Specifically, we will ask whether transcription patterns that determine cell states are determined, not only by developmental history or by environmental influences, but also by regulated expression of DNA binding proteins. The factors that will be considered differ from conventional transcription factors by their anticipated short or highly redundant DNA recognition sequences (2-4 bp), which are expected to occur every few hundred base pairs apart throughout the genome. Because of their apparent lack of specificity, factors of this kind have not attracted research interest. We propose to clarify the functional significance of low-complexity DNA sequence motifs by analyzing the impact of the sequences on gene expression as well as by characterizing in detail the DNA binding proteins that mediate these effects.

A role for proteins that recognise short, frequent sequence motifs in setting up epigenetic landscapes. DNA associates with nucleosomes to form chromatin, which is available to conventional transcription factors (TFs) but also to proteins binding short sequence motifs. The significance of CpG binders (small yellow circles) has recently emerged, but other such proteins (e.g. AT-run binders; blue and green hexagons) are relatively unstudied. Our hypothesis is that these proteins recruit chromatin or DNA modifying complexes (modifiers; larger circles) based on features of DNA sequence.