POLYCOMB REPRESSIVE COMPLEX 1 IS REQUIRED TO MAINTAIN STEM CELL IDENTITY AND TO PRESERVE ADULT TISSUE HOMEOSTASIS.

Polycomb Repressive Complex 1 (PRC1) is an evolutionary conserved transcriptional repressive complex, fundamental for lineage fate decisions and maintenance during development. PRC1 acts by depositing a moiety of Ubiquitin on lysine 119 on histone H2A, promoting nucleosome compaction and transcriptional repression. Cell identity is a fundamental feature, not only during development, but it has to be maintained throughout the entire individual lifespan. Importantly, loss of cell identity is associated with pathologies, primarily with cancer. We recently described that, in homeostatic condition, PRC1 loss of function in LGR5 expressing intestinal stem cells, led to severe defects in tissue maintenance due to loss of stem cell identity and stem cell self-renewal. This places PRC1 as a fundamental complex in stem cell preservation. In this context, PRC1 is necessary to repress non-lineage specific transcription factors, whose upregulation not only perturbs the transcriptome of stem cells, thus leading to identity loss, but also impairs the transcriptional control of the WNT pathway that is essential for stem cell self-renewal. The landscape is even more complicated by the evidence that tissue context plays a critical role in protein function. In pathological conditions, primarily in cancer, several reports have described opposite roles for epigenetic players, including PRC1 subunits, depending on the cancer type. This highlights the importance of context dependency for the correct choice of the therapeutic approach. This opens up the possibility that PRC1 function, or PRC1 activity loss, could be different among different tissue types. To address this point we evaluated PRC1 activity and function in a different LGR5 expressing stem cell populations that derives from a different embryonic layer, the hair follicle, analyzing the phenotype of loss of PRC1 activity in this context and comparing the transcriptional outcomes in the different stem cell populations to describe the influence of context on PRC1-loss. Our data support a general role of PRC1 in stem cell identity maintenance, that is accomplished through the regulation of the same targets. However, we show that, differently from intestinal stem cells, PRC1 activity loss in the hair follicle leads to the activation of a specific epidermal program, showing that the pool of transcription factors present in different stem cell population alters the transcriptional outcome of PRC1 loss. To add a layer of complexity to the Polycomb field and to its role in identity maintenance, PRC1 is composed by several subunits that define at least 5 different biochemical sub-complexes. These complexes are specified by 6 different mutually exclusive PCGF proteins (PCGF1-6) that determine the ancillary subunits composing the complexes. Their role in embryonic development is matter of several studies, however their involvement in adult tissue maintenance is still obscure. Exploiting different PCGFs conditional knock out mouse models we aim to address the specific role of different sub complexes in the maintenance of tissue homeostasis, in order to define the contribution of these Polycomb complexes in the phenotypic outcome observed in PRC1 loss of function intestinal and hair follicle LGR5 stem cells.