TRGE-ZEB-IRG · Transcriptional regulation of gene expression during cell differentiation and oncogenic transformation

Final Activity Report Summary - TRGE-ZEB-IRG (Transcriptional regulation of gene expression during cell differentiation and oncogenic transformation)

This project investigated one of the most important issues in biomedical research today, namely the regulation of gene expression in the context of human disease and, more specifically, cancer. Organs, tissues and cells in our body specialise on different functions as result of specific patterns of gene expression. Genes are regulated through different mechanisms, the most important one being transcriptionally: sets of certain proteins (known as transcription factors) bind to some areas in their sequence (known as promoter regions) to activate them or repress them. While there is a quite precise knowledge about how nuclear factors regulate gene expression through transcriptional activation, the mechanisms for transcriptional repression are only now begun to be understood. This project aims at understanding how transcriptional repression regulates gene expression in the context of both normal cellular functions but also during pathological conditions such as cancer. For this purpose we have chosen as model a family of transcriptional activators known as the ZEB family (ZEB1 and ZEB2). Over the course of this project we have embarked in three subprojects. 1) We have found that ZEB1 repress gene expression by binding to another protein called BRG1. BRG1 has been previously involved in cancer and our research has linked for the first time to the functions of the ZEB transcription factors. 2) We have also studied the expression of ZEB1 and ZEB2 in hematopoyetic organs (those where blood cells are formed, mature or reside) and investigate how levels of ZEB change during oncogenic stimuli. Studies by our group and others have demonstrated that ZEB proteins act as potential suppressors of tumours. In other words, when ZEB proteins are missing (or mutated), cells become cancerous. In coming months we will therefore study the expression of ZEB1 and ZEB2 in leukaemia and cancer. 3) Finally, we have also studied the expression and function of ZEB proteins during muscle formation and differentiation. We found that ZEB1 and ZEB2 are expressed very early in muscle formation and that their levels of expression are important for muscle cells to differentiate and form muscle fibres. On-going experiments are also currently in progress to determine the role that ZEB proteins play in certain muscle pathologies. Achieving the aims proposed in this research proposal will further our understanding of the transcriptional networks regulating gene expression. But it will also have larger implications; a more precise knowledge of the molecular mechanisms by which proteins inhibit transcription will contribute to open new avenues to interfere with their function and hence lead to translational applications. According to the World Health Organization, cancer accounts for 20% of all deaths in Europe, killing almost two million people every year. The molecular models chosen for this project, ZEB proteins, have key roles in human pathology having been involved at the molecular level in some of the most common types of cancer in Europe (e.g. lung, intestine, breast). In this regard, it is equally relevant to highlight that the host institution (IDIBAPS) leads Spain in applied research and is among the top ten centres in Europe in translational scientific production and the development of clinical trials for new medicines. Therefore, implementing this project at IDIBAPS has a high potential for the transfer of basic research into translational applications and the development of new approaches to the diagnosis and treatment of human diseases, especially cancer.

Data: CORDIS, © European Union