Homeodomain transcription factors in vertebrates: working together to make a difference

How do different anatomical features develop with remarkable precision along the body axis of each animal species? We know that this process is determined by a group of proteins belonging to the Hox family. The Hox proteins read and execute instructions encoded in the genome. Each member of the Hox family appears in a well-defined territory of the developing embryo, and recognises specific instructions (most likely DNA sequences) contained in the genome. A puzzling finding is that the Hox specificity, which is central to developmental programs, is entirely lost in a test tube, where all Hox proteins recognise similar DNA sequences. Thus some other essential unknown biochemical factor must be present in the developing embryo. This project will identify Hox functional targets in the genome, and thus reveal the mechanisms that allow Hox proteins to control anatomical development. We will apply state-of-the-art experimental technologies and develop new computational methods to investigate systems where Hox proteins control development and their malfunctioning causes disease. Collectively, these results will identify the fundamental mechanisms that underlie anatomical development in vertebrates and will cast light on how their malfunctioning can result in diseases.

The remarkable diversity of the anatomical features appearing along the body axis of all animals is achieved through differential regulation of gene expression programs. Hox transcription factors (TFs) are at the core of this process. However the highly specific gene expression programs directed by different Hox proteins in vivo stand in sharp contrast to their general lack of DNA-binding specificity in vitro. How do Hox proteins achieve their specificity? We will build on our recent discoveries to answer this baffling but fundamental question. Using vertebrate model systems, we will apply a combination of epigenomic, transcriptomic and TF binding profiling to study Hox TFs directly in the areas where they operate. We will develop new computational methods to jointly analyse multiple datasets and uncover TF combinatorial binding patterns. This approach will identify the functional binding of different Hox paralogs genome-wide and will define the mechanisms that determine Hox specificity. Collectively, these results will reveal fundamental mechanisms underlying development, disease and evolution in vertebrates and will provide predictive, testable models of TF functional binding.

This project tackles a fundamental question in biology, namely how do animal species form their diverse anatomical structures?
Our results will be of interest and benefit to multiple parties. Understanding how Hox transcription factors (TFs) operate will clarify how the remarkable diversity of anatomical features along the body axis of animals is achieved, a fundamental goal in developmental biology. In addition Hox TFs are shared by diverse animal species, which display and an astonishing variety in the anatomical structures controlled by these TFs. Thus, defining how Hox TFs operate will also represents a fundamental step forward in our understanding of evolution. Clarifying the fundamental mechanisms that control development and organogenesis will eventually pave the way for the development of stem cell and regenerative medicine approaches targeting new methods of treatment of degenerative diseases, cancer and other pathologies. Hox TFs continue to be expressed into adulthood, where they function in various physiologic and pathologic processes. This project investigates the changes determined by Hox TFs that transform normal blood cells into leukaemic cells: our results will provide insights into the behavior of leukaemic cells and the disease causative mechanisms. This will translate into the possibility to develop new drugs. All of the above will have an important impact on society (the health and well-being of individuals and families). This project includes the development of a new method to facilitate predictions of TFs combinatorial binding. This will provide a valuable new research tool for the community and improve our understanding of gene expression and the functions of the non-coding genome. The interdisciplinary nature of this study will provide opportunities to train junior researchers in the use of next generation sequencing and downstream analyses. Acquiring these highly in-demand skills will eventually benefit the UK research base. To maximize the benefits of our research, we will increase its openness and accessibility and store all data in public online repositories, where they will be freely available to the scientific community. We will also engage with schools, science festivals, local communities and exhibitions, to increase public awareness in the field of genomics research. Translational genomic research is playing an increasingly important role in the diagnosis, monitoring, and treatment of diseases. These advances also raise profound ethical, legal, and social issues related to the use (and possible abuse) of genomic information. Promoting the public understanding of genomics is therefore not only important to support research, but also to promote the changes in society that must accompany scientific and technological developments.