Extended Data Fig. 8. A model explaining the emergence of epigenetically initiated cancers.

The model is based on the well-known Waddington landscape depicting a marble rolling down a slope with multiple choices of trajectories that depend on the hills and valleys encountered on their path. This scheme is a metaphor for the multiple possible cell fates that can arise from a single cell representing the zygote and is frequently used to signify that epigenetic inheritance contributes to the stable transmission of cell fates, once they are determined by intrinsic and extrinsic signals. In the context of this work, we posit that Polycomb components contribute to shaping the landscape and allow for multiple normal cell fates to be established and transmitted through the developmental process. In normal development, the cells (in green) at the top of the hill will move down during differentiation in order to acquire normal fates (left panel). Upon depletion of a Polycomb component, such as the PRC1 subunits PH or PSC, the landscape is modified (center panel). If depletion is stably maintained, the modified landscape forces cells to take a path that is both aberrant and intrinsically stable, inducing cancer formation through loss of cell differentiation, loss of cell polarity and sustained proliferation (upper right panel). If Polycomb protein levels are restored, the landscape returns to its original shape. However, if restoration of the landscape occurs after cells have already chosen an aberrant route (represented by the marble in the middle of the landscape), they will no longer be able to find the healthy trajectory and will be obliged to choose from a limited set of possibilities in a diseased cell space. This may ultimately lead to the maintenance of tumour phenotypes. In addition to the Waddington landscape panels, gene panels are added, representing a putative molecular explanation for the phenomenon described here. The chromatin and functional state of reversible and irreversible genes are shown in each condition. In a physiological condition (left), both categories of genes are bound by Polycomb components and are decorated by repressive histone marks, such as H3K27me3. Upon depletion of Polycomb components such as PH, both the Polycomb complexes and their histone marks are lost and Polycomb target genes acquire active histone mark such as H3K27ac and become transcribed. At irreversible genes, transcriptional activation is dependent on the JAK–STAT signaling pathway transcription factor STAT92E (top right). Upon PRC1 re-establishment, the repressive mark and PH binding is globally recovered. However, chromatin stays open at specific sites that regulate irreversible genes, in which a DNA motif bound by the main JAK–STAT effector STAT92E is enriched. STAT92E target genes include proliferation components and zfh1, which encodes a transcription factor that represses transcription of a set of genes involved in cell differentiation. The combined, self-sustaining induction of cell proliferation and loss of differentiation induces tumorigenesis even after restoration of normal levels of Polycomb proteins on their target chromatin (bottom right, see also Fig. 5g).