DIFFERENT EZH2 ISOFORMS ARE EXPRESSED IN PANCREATIC CELLS

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Our laboratory studies the role of chromatin complexes in the silencing of tumor suppressor genes during pancreatic cancer development. HP1, our recently published model (NCB) for epigenetic regulation, predicts that the Histone Code, which mediates these changes so characteristic of cancer, requires both activating and silencing subcodes. These subcodes are, similar to the Histone Code, regulated by extensive posttranslational modifications. This study is focused on unraveling the EZH2-mediated silencing subcode. EZH2 is a protein that provides histone H3 K27 methylase activity to the polycomb complexes, which are mediators of long-term gene silencing in stem cells, embryonic development, and cancer. However, the regulation and functional characterization in pancreatic cell biology, development, and diseases such as pancreatic cancer remain to be established. We find that pancreatic cell lines express two alternative spliced EZH2 forms, one containing 751 amino acids (EZH2a), the best known EZH isoform, and the second consisting of 707 amino acids (EZH2b), previously uncharacterized. The existence of two different EZH isoforms suggests that they may have different functions or undergo alternative modes of regulation in pancreatic cells. Extensive mapping of posttranslational modifications of these two EZH2 isoforms demonstrates that these two proteins are capable of undergoing extensive posttranslational modifications, suggesting a potential subcode similar to the one recently described for HP1. In addition, EZH2a has additional ST/Q motifs, which are phosphorylated by PIKK family members such as ATM, ATR and DNA-PK, implicating this isoform, and not necessarily EZH2b, in DNA repair pathways. Thus, we here describe for the first time that: 1. The pancreas expresses two different EZH2 isoforms, 2: Evidence exists of a polycomb subcode that, similar to HP1, may work by undergoing differential posttranslational modifications, and 3: EZH2a is more likely to participate in DNA repair than EZH2b. Together, these results improve our understanding of the potential mechanism of chromatin dynamics as it relates to gene silencing and DNA repair in the pancreas.