Evolutionary ancient transcription factors: master keys to unlock lineage differentiation?

Our body contains hundreds of different cell types. All these cells carry the same set of genetic instructions, but perform very different functions depending on which genes they decide to express. Therefore, control of gene expression is key to the identity (and function) of each cell. Gene expression is controlled by a class of proteins called transcription factors (TFs). It is well established that the generation of specific cell types requires the presence of certain TFs called lineage-specific TFs, exclusively restricted to a specific cell type or its progenitors. However, addition of a set of lineage-specific TFs is not sufficient to transform a cell into the cell type that normally contains that set, suggesting that further ingredients are required for differentiation. Our preliminary work indicates that a family of evolutionary ancient TFs, expressed in most cell types, function as master 'keys' to unlock cell differentiation. We will use state-of-the-art experimental technologies to understand how these regulators contribute to specific cells states and test if they can help lineage-specific TFs to achieve the desired cell types. The ability to reprogram endogenous fibroblasts into cell types of interest has important implications for regenerative medicine and disease modelling. Collectively, these results will provide new insight into how cell states are established, with direct relevance for generating specific cell types from stem cells or even from other adult cell types.

Control of gene expression determines and maintains cellular identity and function in embryonic development and adult tissue homeostasis. Lineage-specific transcription factors (TFs) recognise lineage-specific enhancers to orchestrate the precise gene expression programs that determine cell fate. However, with few exceptions, lineage-specific TFs are typically unable to efficiently reprogram cells into their specific cell type. The evolutionary ancient MEIS TFs are widely expressed and essential for the differentiation of lineages as diverse as cardiac and neural, and their binding dynamics can effectively predict tissue-specific enhancer activities. We propose that MEIS TFs function as universal keys that unlock the lineage-specific transcriptional programmes producing specific cell types. We will test the hypothesis that these regulators have distinctive properties that not only allow them to select lineage-specific enhancers, but also facilitate their engagement in transcription hubs, which is key to activate lineage-specific transcription. We will combine a tractable model of cell differentiation (human embryonic stem cells) with super resolution microscopy to study transcription dynamics at lineage-specific genes. We will use state of the art, quantitative proteomics to elucidate the molecular features that distinguish these regulators from lineage-specific TFs and identify modular units to engineer artificial TFs. Finally, we will directly assess the ability of MEIS TFs to unlock cell differentiation by direct reprogramming of human skin or cardiac fibroblasts to cardiomyocytes. Collectively, these results will resolve the complexity of mammalian TF networks that determine cell fate and provide new insight into how healthy and diseased cell states are established, with implications for efficient cell reprogramming and the generation of specific cell types.