Mechanistic insights into the periodic control of transcription in the mammalian cell cycle

All of us develop into complex human beings containing millions of cells from a single cell created by fertilization of an egg. To transit from this single cell state, cells must continually divide into two cells, and in doing so pass a copy of their genetic blueprint (ie their DNA) to the new cells. This process is generally referred to as cell division. It is therefore critically important to understand the fundamental mechanisms that control this process. Conversely, as we age, cells become incapable of division and become "senescent". This creates a problem as we can no longer generate new cells to replace old or damaged cells. Conversely, hyperactivation of cell division leads to cancer. Indeed, cancer is a disease caused by the malfunction of "normal cells" in your body, and one of these malfunctions involves the onset of cell division. If this process goes unchecked, large masses of cells develop which accumulate more damage, and ultimately give rise to tumours. Thus understanding this critical process of cell division in normal cells and ultimately how this goes wrong in cancers is vitally important. This project aims to understand how one key regulator, FOXM1, works to control cell division. The abundance of this regulator is increased in cancer cells but is decreased in ageing cells, placing it at the nexus of control of these two important processes. FOXM1 does not work alone but has partners which help it to decode specific subparts of the genome in a process known as transcription. Here, we will study known partners and identify new partners for FOXM1. We will investigate how they work together to control cell division. This will provide a platform for establishing whether the mechanisms we uncover are relevant in the context of ageing or cancer and might lead to the development of therapeutic strategies.

Cell division is one of the fundamentally important cellular processes. Stringent control over the cell cycle regulatory machinery is essential to ensure that the correct number of cells is produced at the right time. This is critically important in many core biological processes including developmental events, and immune responses. Loss of this control is one of the classical hallmarks of cancer where cells become hyperproliferative. Conversely loss of proliferative capacity is one of the hallmarks of ageing or senescent cells. One key element of cell cycle control is exerted at the transcriptional level, where the expression of key cell cycle regulators is controlled in a periodic manner in a succession of waves. The transcription factor FOXM1 has been tightly linked to controlling transcription during one of these waves; the G2 and M phases of the cell cycle. Due to its overexpression in a large number of different human cancers, the forkhead transcription factor FOXM1 has been strongly implicated in tumourigenesis and it is thought that one major mode of action in this context is through promoting cellular proliferation. Conversely downregulation of FOXM1 is associated with cellular ageing and senescence. Recent mechanistic studies have uncovered one major way in which FOXM1 is recruited to chromatin. However, despite these advances, our mechanistic understanding of FOXM1 function is currently far from complete, and it is unclear how it acts at different subgroups of its target genes. The overall aim of this project is to use a systems-wide approach to establish how FOXM1 is recruited to chromatin and controls the activity of its target gene network. Preliminary results suggest that there are likely several distinct sets of target genes that are regulated in a different manner by FOXM1. Here we wish to uncover the different mechanisms involved.

Academic beneficiaries: As described in the 'Academic beneficiaries' section, these will include UK and international researchers in the following biological science fields: Gene regulation, cell cycle control, chromatin regulation and transcription factor function. Academic beneficiaries from other disciplines will include clinical researchers studying the molecular basis to cancer. Finally, bioinformaticians and mathematical modellers studying dynamic transcriptional networks and creating regulatory maps of the cell cycle cell cycle will benefit from our research as we aim to identify novel regulatory nodes.

General public: In terms of the wider public beneficiaries, the long term impact of this project will likely be for cancer patients. In this project we will focus on FOXM1, a protein that is overexpressed across a broad range of cancers. We will uncover novel mechanistic aspects of FOXM1 function. Other work in the lab will study the relevance of our findings in the context of oesophageal adenocarcinoma. This disease is one of the commonest cancers, and yet has a very poor prognosis and survival rate. Part of this is due to the late presentation of the disease but our lack of molecular knowledge about this disease is also a barrier to developing successful therapies. In addition to our mechanistic work, our studies may also reveal cohorts of genes that have useful prognostic significance for oesophageal and other cancers and hence might have additional clinical relevance. Importantly, due to the widespread overexpression of FOXM1 across a wide range of cancers, our work is likely to be of potential benefit to a much broader number of patients. In addition to cancer patients, the other beneficiaries might be the ageing population, as FOXM1 has been previously shown to be a key regulator of the ageing process. Further knowledge of this protein might therefore impact on our understanding of this process, and our ability to modulate this.

Public sector: In terms of the public sector, then the biggest impact is likely to be on the NHS. Any new mechanisms that we identify, might lead to either new prognostic targets being identified in the context of cancer, and ultimately might inform the development of new treatments of either cancer or reversing cellular ageing. Training will be provided to medically trained MD students who will develop clinically relevant projects based on the findings of this study.

Industry: Many pharmaceutical companies are attempting to develop anti-cancer drugs. The identification of new targets can drive new drug discovery programmes. Indeed, inhibitors of FOXM1 function are currently being developed and their relevance to breast cancer treatment are currently being explored. Further understanding of how FOXM1 functions will open up new opportunities for developing inhibitors which act in a different manner, with the potential to further develop these into successful anti-cancer agents. This project will also involve the use of many cutting edge technology and as such will provide an opportunity of training the next generation of researchers through exposing undergraduate, postgraduate and postdoctoral students to these approaches.