Resumen de Stochastic modelling of epigenetic regulation: analysis of its heterogeneity and its implications in cell plasticity
In this thesis, we aim at understanding the importance of epigenetic regulation (ER) in cell fate decisions and transitions. In order to address this issue, we first formulate a stochastic model of epigenetic regulation. Within this model, we focus our discussion in cell reprogramming, i.e. the system moves from the differentiated epi-phenotype, characterised by differentiation(pluripotency) ER system open(closed), to the pluripotent epi-phenotype, where the ER system for differentiation(pluripotency) is closed(open).
In particular, within the intrinsic heterogeneity existing in ER systems, we identify the appearance of two relevant scenarios: the resilient scenario, where reprogramming cannot occur, and the plastic one, which is the one allowing for the switch from the differentiated epi-phenotype to the pluripotent epi-phenotype. The latter, which is characterised by exhibiting epigenetic plasticity, has been linked to ageing. In fact, when just ageing effects are considered in the ER model, the system displays a ‘healthy’ plasticity, where the stem-cell like properties can be acquired, but then, the ER system can go back to the differentiated epi-phenotype. This scenario may be related to regeneration and rejuvenation of tissues. Nevertheless, when ageing is considered along with epigenetic dis-regulations, which are likely to occur withing ageing cells/tissues, the plastic state leads to a pathological plasticity, where stem cell features are acquired irreversibly. This scenario is the one which may predispose the system to cancer, as it implies the accumulation of undecided epi-phenotypes with the pluripotency ER system sustained in its on state.
In order to further analyse this issue, we formulate a general framework for the study of a combined epigenetic regulation-gene regulatory network (ER-GRN) stochastic multiscale model, which we later focus on our particular case of interest, i.e. a 2 gene regulatory network with one gene promoting differentiation and one gene promoting pluripotency. When analysing the ER-GRN model formulated, we show that the role played by ER is central since it allows the GRN to switch state, i.e. cell fate transitions from the differentiated phenotype to the pluripotent one (reprogramming) or vice versa (differentiation).
The ER-GRN model allows to identify which ER systems are responsible for locking the cell in a stem cell like state and our formulation allows us to design epigenetic-based strategies able to obtain differentiation-primed cells from differentiation-resilient cells. Such strategies are of key relevance in the treatment of cancer and other age-associated diseases.
