OCTOBER · Control of cell identity in pluripotent and germline cells by OCT4 orchestration of chromatin binding and enhancer regulation

Control of cell identity in pluripotent and germline cells by OCT4 orchestration of chromatin binding and enhancer regulation

Mouse embryonic stem cells (ESCs) are characterized by two defining features: the ability to undergo limitless cell divisions in which the daughter cells posses exactly the same properties as the mother cell (a process referred to as self-renewal), and the capacity to change properties to give rise to all the cells of the developing mouse embryo (a process referred to as differentiation). Although ESCs have been studied since they were first reported in 1981, the molecular mechanisms underlying the choice between self-renewal and differentiation have not been completely described. OCTOBER is a multidisciplinary project that aims to provide new insight into this unresolved problem, focusing on the differentiation of ESCs into primordial germ cells (PGCs), progenitors of gametes. One of the main characters in this pathway is OCT4, a transcription factor (TF) that can bind specific regulatory regions in the genome to modulate gene expression of specific targets. Interestingly, OCT4 has been reported to be essential for the ESCs to maintain their pluripotency but it is highly expressed both in ESCs and PGCs at comparable levels. This observation leads to the question of whether the same protein – OCT4 – may exert specific functions in distinct contexts, possibly by interacting with different regulatory regions in the genome. A potential OCT4 binding protein that may contribute to widespread differential localisation of OCT4 to regulatory sites in chromatin during the differentiation of ESCs is OTX2. This protein has previously been reported to re-direct OCT4 to bind at one specific location (the Fgf5 locus) but whether OTX2 acts more broadly than this is not known. OCTOBER uses recently developed techniques to identify binding sites of OCT4 and OTX2 at chromatin while modulating the expression level of either of the two TFs. As an additional aim, the specific role of OTX2 in the choice of somatic vs germline differentiation has been studied. The overall objectives of OCTOBER were to generate new knowledge on the mechanism of gene expression and regulation in the differentiation of ESCs to PGCLCs, with a focus on the role of TFs, and to further develop and/or acquire technical and transferrable skills that will help me become an independent leader in the field of genomics and stem cell biology. Although the results are not published yet, the action was successful regarding both objectives. While the focus of OCTOBER is mainly on basic molecular mechanisms, the results will generate insights into the mechanisms of early germline formation. This will provide new information that may assist development of future approaches to treat both infertility and germ cell tumours. In conclusion, OCTOBER is a successful action that generated and will continue to generate new knowledge in the regulation of gene expression in mammalian stem cells and, at the same time, provided me with essential skills for my next steps toward an independent career.

Data: CORDIS, © European Union