The study utilised bulk-tissue and single-cell transcriptomics and epigenomics data from 85 unique human donor eyes to understand the molecular changes that occur as AMD develops. Tissue transcriptomes of early, intermediate, and two types of advanced-stage AMD were analysed, resulting in the identification of 23 significant genome-wide loci that are differentially methylated in AMD. Over 1,000 differentially expressed genes were found across disease stages and distinct Müller cell states in AMD-affected eyes. The research highlights causal gene upregulations and underlying genetic risks for AMD.
One intriguing finding of the study is the identification of different clusters of Müller glia cell states, including basal, AMD, and gliotic states. The basal Müller cluster predominantly came from control samples, while the AMD Müller cluster largely came from AMD donors. The study authors note that although Müller gliosis is a common feature in retinal diseases and injury, the AMD Müller cluster did not show higher expression of gliosis markers, which is different from retinal injury models often used in AMD research. This suggests that a deeper understanding of the disease state Müller glia is needed for potential therapeutic strategies involving reprogramming of basal or gliotic Müller cells, as these may not be suitable for the AMD-like state.
Furthermore, the study found that the gliotic state appears to be a crucial intermediate between normal Müller glia and the stem cell identity in retinal regeneration. This finding suggests that as research on retinal regeneration translates into therapeutic strategies, a better understanding of the disease state Müller glia is necessary.
CHROMATIN ACCESSIBILITY
The study also compared control and AMD donors but found no genome-wide significant differences, and no overt differences between control and AMD samples at cell type or subtype levels. This contrasts with a previous study in 2018 by John Hopkins researchers, which found a global reduction of open chromatin in the AMD disease state using ATAC-Seq analysis. However, the Genentech researchers did not observe a corresponding shift in chromatin accessibility in their study, suggesting that previous findings of changes in chromatin accessibility in bulk analysis may have been confounded by cell death and nuclei from non-disease-related cell types.
The Genentech researchers, in collaboration with colleagues from the University of Utah and the State University of New York at Buffalo, have addressed previous assumptions and confounding research attempts, and identified a robust number of relevant gene mechanisms related to AMD. These findings are expected to form the basis for future research on the subject.
AMD is a significant global health concern, affecting millions of people worldwide. It is a leading cause of blindness, and currently, there are limited treatment options available. Therefore, identifying potential drug targets for AMD is crucial in developing effective therapies to address this condition. The study by Genentech and its collaborators sheds light on the molecular changes that occur during AMD development and provides valuable insights into the gene mechanisms involved in the disease.
The study's findings on the different clusters of Müller glia cell states and the role of the gliotic state in retinal regeneration may have important implications for future therapeutic strategies. Understanding the distinct gene expression patterns in different stages of AMD and the involvement of Müller glia cells could potentially lead to the development of targeted therapies aimed at modulating these specific mechanisms.
