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Adeline Berger, Mathieu Quinodoz, Xavier GERARD, Martial Mbefo, Carlo Rivolta, Yvan Arsenijevic; Bmi1 loss delays retinal degeneration by decreasing H3K27me3 accumulation, cGMP level and cell stress response. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4994.
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© ARVO (1962-2015); The Authors (2016-present)
We focused on identifying and characterizing the mechanisms essential to Bmi1 loss-induced photoreceptor survival previously observed in Rd1 mouse model, apart from the reduction of cell cycle reentry events previously described. Based on its role in the Polycomb Repressive Complex 1 (PRC1), we suspected Bmi1 to epigenetically control a transcription program leading to retinal degeneration.
To identify Bmi1 loss induced-deregulated genes and pathways, we compared RNAseq data of Rd1 to Rd1;Bmi1-/- mouse retina. We integrated data from WT mice to assess whether Bmi1 loss was restoring Rd1-disrupted genes or inducing a distinct program. RT-qPCR and immunohistology stainings were performed to validate each candidate gene expression and location in photoreceptors. To further characterize the role of Bmi1 and PRC1/PRC2 complexes, we will continue measuring global and specific changes in H2AK119Ub and H3K27me3 marks (PRC1 and PRC2 specific marks respectively).
Gene Set Enrichment Analysis of RNAseq data revealed enrichment for PRC2 targets, embryonic morphogenesis and phototransduction. As PRC1 and PRC2 are required for long term epigenetic silencing of developmental gene, it is not surprising that Bmi1 loss affects PRC2 target genes and morphogenesis-associated neural genes (e.g. Hox family genes, En2, Zic1). Moreover, H3K27me3 did not accumulate in Rd1;Bmi1-/- photoreceptors compared to Rd1 ones, and the use of EZH2 inhibitors in the Rd1 retina markedly reduced H3K27me3 marks and protected photoreceptors in vivo. Interestingly, several genes involved in the phototransduction cascade were upregulated in Rd1;Bmi1-/- mice versus Rd1 mice, suggesting their involvement in the reduction of cGMP level also observed. Furthermore, our untargeted approach led to the identification of deregulated genes such as IRF5 (see abstract Gerard et al), CDKN2b, EGR1, involved in oxidative stress, cell cycle regulation and eye growth, respectively. BMI1 binding and specific targeting of these genes are currently being assessed.
Our study confirms a role for Bmi1 in controlling photoreceptor death in Rd1 model, and for the first time, identified epigenetic regulation of multiple key pathways involved in retinal degeneration, such as cGMP pathway and oxidative stress. Bmi1 loss also seems to preserve photoreceptors by regulating the expression of developmental neural genes.
This is a 2020 ARVO Annual Meeting abstract.
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