The establishment of correct cellular fate is at the basis of normal development of any multicellular organism. Developmental processes continue for the entire life of any organisms to sustain homeostasis and tissue regeneration from environmental insults. The correct control of cellular fate is frequently deregulated in diseases where cancer can be considered one of the best examples. Neoplastic development always involves a loss of cell identity constraints and the acquisition of new features that allows disease progression. This entails the acquisition of both genetic and adaptive (epigenetic) features, which frequently comprise the same mechanisms that control development and regenerative proprieties.
Cell identity is established and preserved by the set-up of specific transcription programs allowing a correct use of the genetic information. Simplifying a complex mechanism, this involves both the activation of the “correct” genes while silencing of the rest of the genome. This can be achieved by coordinating the activity of DNA binding transcription factors together with the modulation of the local structure of chromatin.
In such scenario, Polycomb proteins represents the major repressive system by which genes are maintained transcriptionally silenced. This includes a large family of proteins with distinct biochemical features that execute their activity forming large multiprotein complexes that modify the chromatin environment to maintain repression. Their activity is essential for several developmental processes and different members of this family are frequently targeted by mutations that affect their activity in several human diseases. This includes, with high frequency, human tumors where components of the Polycomb machinery are targeted by gain and loss of function mutations in a tissue dependent manner. Although the Polycomb machinery can be reconciled in two major enzymatic activities, these are characterized by an high biochemical heterogeneity. Several distinct forms of Polycomb complexes exist with distinct biochemical features whose role remains poorly understood.
This project aimed to generate new knowledge related to the specific molecular and biological function exerted by these different activities. This has been achieved by combining the use of mouse embryonic stem cells with the development of genetic mouse models to characterize their functional properties in the specific context of adult tissues homeostasis and stem cell identity.
The project has dissected the specific roles of distinct Polycomb ensembles and their molecular mechanisms. The results of this project led to different publications, demonstrating how different activities exert compensatory but also specific roles in regulating gene expression. This work highlighted context specific regulatory mechanisms. In vivo, this translates in specific contributions to define lineage identities and tissue regeneration.
Overall, this work has generated important knowledge advancements related to how developmental and tissue regenerative processes are regulated by repressive chromatin features. Importantly, since these molecular mechanisms play specific roles also in the context of different human pathologies, the uncovering of these molecular details can provide a better disease understanding and uncover new vulnerabilities with therapeutic value.
