The PRC2 enzyme complex is responsible for depositing the epigenetic mark H3K27me3, which is strongly associated with gene silencing. PRC2-mediated gene silencing is essential during development to limit the expression of genes associated with later developmental stages.
PRC2 is a multisubuit complex comprised of the obligate members EZH2, which is the catalytic subunit, as well as the scaffolding and recruitment partners EED and SUZ12. The enzyme complex will have a number of additional members that display unique properties in vivo and in vitro.
The occurrence of several of these accessory proteins are commonly mutually exclusive with one another in the PRC2 complex and appear to define critical biological parameters, including recruitment to chromatin where it contributes to the regulation of gene expression.
The regulation of PRC2-mediated gene silencing is not well studied. The gaps in our knowledge include transcriptional regulation of the enzyme components, the upstream signaling pathways that regulate PRC2 function, and the factors that drive PRC2 recruitment to chromatin.
A major PRC2 isoform consists of EZH2, AEBP2, SUZ12, EED and RBBP4 and this complex is highly associated with the progression of a number of tumors. High expression of several PRC2 subunits associate with poorer patient outcomes in some settings, highlighting the clinical relevance of understanding these transcriptional dynamics. In addition, there are several unresolved questions surrounding the activity of PRC2. For example, the recruitment of PRC2 to chromatin in pluripotent stem cells is frequently observed to be inversely correlated with 5mC. We discovered that in vitro the opposite was true; recombinant PRC2 actually displays a strong binding preference for 5mC-substituted DNA. Furthermore, unlike in pluripotent cells, in cancer cells PRC2 co-occupancy with 5mC can be observed at numerous loci and the TERT proximal promoter is one of these sites.
Another unresolved question surrounds the well-recognized persistence of PRC2 on chromatin in the apparent absence of the high levels of H3K27me3; what regulates this seemingly contradictory scenario? The TERT proximal promoter in certain cancer cells is one locus where PRC2 persists but which fails to accumulate high levels of H3K27me3. Thus, the specific interaction between TERT and PRC2 provides an opportunity to understand both TERT regulation and PRC2 biology. Given these unresolved issues, the following questions represent major research interests:
What factors drive PRC2 component expression in cancer?
How does 5mC in vivo influence PRC2 recruitment to genomic loci in cancer cells?
What counteracts PRC2 enzymatic activity at certain chromosomal loci?
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