Deciphering the Mechanisms of Modulation of DNA Accessibility in Chromatin: Discovery of Novel Pioneer Transcription Factors

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In eukaryotic cells DNA is packed in the form of chromatin, about one meter of the DNA should fit into the nucleus of the size of several microns. At the same time, DNA should be dynamically accessed during the transcription and replication processes with high spatiotemporal precision. This dilemma has been puzzling researchers for many years. It has been argued that this extremely high degree of DNA compaction can be achieved by engaging different structural and regulatory macromolecules at multiple levels of chromatin organization, where nucleosomes represent elementary building blocks of packaging. Some macromolecules can infiltrate the relatively closed chromatin states and specifically bind to nucleosomes. There are about two thousand factors which control the expression of their target genes in human. Some of them include well-studied conventional transcription factors that bind to accessible DNA, whereas others, so-called pioneer transcription factors, can target compact chromatin. Pioneer transcription factors may directly recognize their binding sites on nucleosomes, make DNA more accessible and cooperatively engage other factors for transcription activation. The vast majority of human pioneer transcription factors are not known, the locations of their binding sites, mechanisms of binding and regulation remain to be determined. Using large-scale experimental data on nucleosome positioning, transcription factor binding sites and three-dimensional structural data, this research program will develop various computational techniques including molecular modelling, molecular dynamics simulations and machine learning to decipher physicochemical mechanisms responsible for pioneer transcription factor binding and regulation. This work will create cutting-edge computational open-access tools and will advance a conceptual framework of chromatin regulation at the local genomic scale. This can open new avenues for the design of innovative and promising epigenetic therapies. The HQP training will produce researchers which are capable to work in interdisciplinary fields and have state-of-the-art qualifications in computational modelling and machine learning.