Guided activation as a model for transcription factor networks determining cell fate

The hundreds of different cell types in our body contain the same genetic instructions but produce different proteins because they express different genes. Gene expression is controlled by a class of proteins, called transcription factors (TFs). Therefore, TFs determine the differences in cell types and, when malfunctioning, cause a wide range of disease states. TFs recognize precise sequences in the genome to find their target genes. It is well established that TFs access their target genes much more efficiently when they operate in groups, but we still do not understand how these clusters of TFs, once bound to their target sequences in the genome, activate gene expression. We will address this fundamental question in biology through state-of- the-art experimental technologies and computational methods. Collectively, these results will provide new insight into how cell states are established, with direct relevance for efficient cell reprogramming and the generation of specific cell types.

Accurate gene expression is fundamental to life. Gene expression is controlled by transcription factors (TFs) binding to regulatory elements in the genome, (enhancers). It is well established that groups of TFs cooperate to facilitate each other's access to enhancers. However, a fundamental question is how these clusters of TFs, once anchored to their target enhancers, recruit co-activators to regulate RNA polymerase II and activate gene transcription. Are the multiple TFs bound to enhancers equivalent in recruiting co-activators, and therefore interchangeable? Or do they contribute different functions? Our preliminary work indicates that tissue-specific TFs harness the activation skills of ubiquitous activators at specific enhancers. The key developmental regulators MEIS are essential for development of many organs (limb, face, eye, heart), and can function as oncogenes. We propose that widespread, low affinity binding of MEIS TFs across the genome provides chromatin with activation potential in many different cell types. Collaborative binding of MEIS TFs with tissue-specific TFs increases MEIS binding affinity and residence time at selected locations, and in turn its ability to locally recruit coactivators. This process allows selective gene expression and determines cell fate. We will combine high-throughput and single locus-based approaches in tractable in vitro systems (human embryonic stem cells) with state-of-the-art computational approaches to study the dynamic recruitment of multiple TFs at cell type-specific enhancers and define their individual contributions to gene expression. This project will clarify how cell-type specific enhancers are selected and activated and how specific cells states are established, addressing a fundamental question in biology and paving the way for efficient cell reprogramming and the generation of specific cell types.

Understanding how transcription factors (TFs) cooperate to activate cell-type-specific transcription will improve our understanding of how cell states are achieved and identify general rules that control gene expression. Therefore, results obtained in this project will be of interest and benefit to genome biologists and developmental biologists. By investigating how regulatory chromatin landscapes underlying cell-type-specific gene expression programs are established, our work has the potential to uncover more efficient ways to harness cell reprogramming and generate high fidelity production of specific cell types, which will be of immediate relevance to stem cell researchers, as well as biotechnology companies developing stem cell-based therapies. TALE TFs are involved in cancer and mutations in genes encoding TALE cause a number of congenital conditions. A better understanding of how TALE TFs operate will help to identify additional causes of cancer and congenital disease and expand clinical diagnostic capacity, which have an important impact on society in terms of improvements to health and well-being. The interdisciplinary nature of this study will provide opportunities to train junior researchers, including undergraduate and postgraduate research students rotating in the lab, as well as postdoctoral researchers, in systems-based approaches and advanced bioinformatics. Acquiring these highly in-demand skills will contribute to the economic competitiveness of the UK. The fast advancement of genomic research is increasingly being translated to genomic medicine, which raises profound ethical, legal, and social issues related to the use (and potential abuse) of personal genomic information. Engaging with the public is therefore vital in opening and maintaining a dialogue between scientists and the public and facilitate the changes in society that must accompany scientific and technological developments.