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Integrated approaches to study gene regulation during cellular differentiation

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The complexities of cell development

Development of a stem cell to its mature counterpart with a specific identity is controlled by complex transcription networks. An EU project has uncovered new mechanisms that direct the cell differentiation journey.

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The 'Integrated approaches to study gene regulation during cellular differentiation' (INTEGER) initiative took a multi-faceted approach to investigate regulatory mechanisms in liver and red blood cells. Seven academic and one industrial partner looked at the master regulators of differentiation — transcription factors. Interaction between genes and the impact of spatial organisation in the nucleus featured highly as another control mechanism. When a cell reaches the end of its maturation phase, its identity has to be retained using cellular memory mechanisms. Cell memory through modifications that don’t affect DNA structure, the sphere of epigenetics, was also investigated. Genomic and proteomic technologies developed to tackle the ambitious INTEGER objectives included analysis of chromosome organisation combined with high throughput sequencing (4C-seq). Scientists' devised methods to map epigenetic non-coding RNA binding sites and to characterise the proteins produced (the proteome). During the differentiation of liver cells, the team identified several amazing control features. Notable are complex cross regulatory methods and 'bookmarking' jobs for transcription regulators keeping regulatory areas open in early development. The scientists incorporated the integration of transcription factor genome-wide occupancy data with epigenomic modifications during blood cell development. This approach led to the identification of distinct classes of genes that share epigenetic and functional characteristics. Mouse embryonic stem cells (ESCs) studies revealed how 'stemness' is maintained and the impact of folding and unfolding in active and inactive X chromosomes. A large number of newly identified interacting proteins are specifically associated with different stages of the transcription cycle in ESCs. Twelve researchers will obtain their PhD qualifications by having participated in INTEGER. Also crucial to the sustainability of the INTEGER project, their training programme included four advanced workshops and a scientific conference. Input from the many external speakers and a cross-disciplinary approach will ensure that the research results will continue to have a significant impact in the field of cell differentiation regulation.


Cell differentiation, embryonic stem cell, epigenetic, transcription factor, cycle

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