Abstract
Purpose :
Bmi1 loss provides strong protection for the retina against photoreceptor degeneration in the Rd1 mouse, through underlying mechanisms that remained to be characterized. BMI1 is a member of the Polycomb Repressive Complex 1 (PRC1), which epigenetically regulates the expression of many genes during development and disease progression. We hypothesized that the loss of Bmi1 induces multiple changes in the transcriptional program of photoreceptors allowing their survival.
Methods :
To identify the genes and pathways deregulated by Bmi1 loss, we compared RNAseq data of Rd1 and Rd1;Bmi1-/- mouse retinas. We also integrated data from WT mice to assess whether Bmi1 loss was restoring Rd1-disrupted genes or inducing a distinct program. We then further investigated pathways involved in photoreceptor homeostasis and cell death. To characterize the epigenetic role of Bmi1, we assessed global or targeted changes in H3K4me3, H3K27Ac, H2AK119Ub and H3K27me3 marks in WT, Rd1 and Rd1;Bmi1-/- retinas.
Results :
Differential gene expression revealed a Rd1;Bmi1-/- specific deregulation of some transcription factors involved in developmental neurogenesis and neuron survival, such as EN2, SIX1, SIX2 and NEUROD6. On the other hand, we observed at least a rescue, in the Rd1;Bmi1-/- mice, of the level of expression of some deregulated genes in Rd1 versus WT. For example, Guca1a and Guca1b, which were downregulated in Rd1 versus WT mice, were even further upregulated in Rd1;Bmi1-/- retinas. Interestingly, this correlated with a decreased accumulation of cGMP, known to contribute to photoreceptor death. The pro-inflammatory factor IRF5, upregulated in Rd1, was also reduced upon Bmi1 loss. Moreover, Bmi1 loss allowed Cdkn2b expression, which inhibits cell cycle reentry, itself described to drive neuronal apoptosis. On a more global approach, we observed in Rd1;Bmi1-/- versus Rd1 mice, an enrichment for gene sets linked to PRC2 members and H3K27me3 mark. We confirmed an epigenetic regulation on some targeted genes either direct or indirect.
Conclusions :
Our study describes the role for Bmi1 in controlling photoreceptor death in a retinitis pigmentosa model, and highlights Bmi1 epigenetic regulation of multiple key pathways involved in photoreceptor homeostasis and survival.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.