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Yvan Arsenijevic, Andrea Prunotto, Carlo Rivolta, Martial Kamdem Mbefo; EZH2 is associated with photoreceptor degeneration and potentially targets miRNAs controlling cell cycle and apoptosis.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3491.
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© ARVO (1962-2015); The Authors (2016-present)
Retinitis Pigmentosa (RP) is a class of hereditary retinal dystrophy associated with photoreceptor loss and blindness. Among several actors mediating cell death, we observed an abnormal cell cycle re-entry in photoreceptors undergoing degeneration in Rd1 mice and identified the Polycomb repressive complex 1 (PrC1) core component BMI1 as a critical molecular factor orchestrating the cell death mechanism. The Bmi1 deletion leads to a marked photoreceptor protection in the Rd1 retina, but independently of the conventional Ink4a/Arf pathways (Zencak et al., 2013), suggesting that BMI1 acts on other targets. We thus studied during the degenerative process the potential role of components of the PCR2 interacting with BMI1, such as EZH2, which methylates Histone-3 to repress gene expression.
We used cross sections from FVB Rd1 and FVB WT mouse retinas at different postnatal ages to screen by immunohistochemistry for the changes of histones marks H3K27me3, which is methylated by EZH2. Photoreceptors were isolated by FACS for WB analyses. We next performed miRNA array analysis from WT and Rd1 retina samples to potentially identify miRNA targeted by EZH2 during photoreceptor degeneration. A new method of Ontology analysis was developed to identify the most promising gene targets of the identified miRNAs.
We observed by WB an upregulation of EZH2 in isolated Rd1 photoreceptors and by immunohistochemistry, a hypertrimethylation of histone 3 (H3K27me3) in photoreceptors before cell death attesting the EZH2 activity. miRNA arrays revealed a very limited number of miRNA candidates which are differently expressed in the Rd1 retina. Interestingly, two miRNAs showing the major expression changes control cell cycle activation as well as apoptosis are known targets of EZH2. These candidates are currently tested in retinal cell cultures.
These results are consistent with our previous findings on photoreceptor death mechanism characterization. Altogether, these data suggest that miRNAs may play a major role during retinal degeneration by controlling apoptosis and cell cycle reentry.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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