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P. W. Chen, L. Sadegh, H. Li; Epigenetic Induction of Dimethylation and Trimethylation at Histone 3, Lysine-4 Residues by the Ocular Microenvironment. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5166.
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Tumor cells that are exposed to the ocular microenvironment undergo epigenetic gene regulation that enables eye-derived tumor cells to escape immune elimination. Methylation at nucleosome core histone 3 at the lysine 4 residue (H3K4) has been correlated to relaxed euchromatin conformation and gene promoter region transcription. This study examined whether the ocular microenvironment induced epigenetic regulation through histone methylation and acetylation at the H3K4-specific lysine residue.
P815 murine mastocytoma cells or human LS174T colon cancer cells were injected into either in the anterior chamber (ac) or subcutaneously (sc) in the flank of DBA/2 mice or NOD-SCID mice respectively. Eye-derived tumor cells and subcutaneous tumor cells were recovered 10 days post-injection. Global histone methylation, histone methyltransferase activity, and histone acetylase activity were determined by ELISA-based assays.
P815 cells and LS174T recovered from the anterior chamber demonstrated an increase in global histone methylation compared to subcutaneous tumors. Examination of histone methylation at H3K4 demonstrated no evidence of mono methylation (H3K4me1) in either eye-derived P815 or LS174T cells compared to subcutaneously derived P815 or LS174T cells. Symmetrical dimethylation (H3K4me2) and asymmetrical trimethylation (H3K4me3) at H3K4 were elevated both in P815 and LS174T eye-derived cell lines but not in subcutaneously derived P815 and LS174T cells. Aceyltransferase activity was elevated in both P815 and LS174T eye-derived cell lines compared to subcutaneously derived tumor cells.
Methylation of the H3K4 residues is a consistent epigenetic mark imprinted on cells exposed to the ocular microenvironment and is independent of cell origin. Lack of H3K4me1 suggests that genes located within this epigenetic mark are not suppressed. Moreover, presence of H3K4me2 and H3K4me3 on chromatin sequences and increased acetyltransferase activity indicates that epigenetic marks imprinted by the ocular microenvironment may promote gene activation that supports ocular tumor immune escape and may be a novel mechanism to maintain immune prvilege.
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