Health
Combining multiple maps reveals new genetic risk factors for AMD
A new study published January 17 reveals new genetic risk factors for adult-onset macular degeneration (AMD) by combining a map of gene regulatory sites with disease-associated loci.th in open access journals PLOSbiology By Ran Erkon and Ruth Ashley Padang and colleagues at Tel Aviv University, Israel. This finding enhances our understanding of the major causes of visual impairment in adults.
AMD is caused by dysfunction of the retinal pigment epithelium (RPE), a layer of tissue sandwiched between the photoreceptors that receive light and the choriocapillaris that nourish the retina. Because of the central importance of RPE in AMD, the authors investigated a transcription factor (a protein that regulates specific genes) called LHX2 that is central to RPE development, based on a team’s analysis of mouse mutants. I started by doing In his RPE from human stem cells he knocked down LHX2 activity and found that most of the affected genes were downregulated. This indicates that the role of LHX2 is likely that of a transcriptional activator that binds to regulatory sites on the genome and enhances the activity of other genes.
The authors found that one affected gene, called OTX2, cooperates with LHX2 to regulate many genes in RPE. Mapping the genomic sites to which OTX2 and LHX2 can bind showed that 68% of the sites that bind LHX2 also bind OTX2 (864 sites in total), and that these work together to drive the activity of a large set of genes. suggests that it is likely to promote Involved in RPE development and functionality.
A common way to find genes that may contribute to disease is to perform genome-wide association studies (GWAS). It identifies genomic sequence differences (called single nucleotide polymorphisms or SNPs) between individuals that co-occur with the disease. This kind of research has been done many times at AMD. However, GWAS alone cannot reveal causal mechanisms. Here, the authors compared LHX2/OTX2 binding data with his GWAS data to identify variations that may affect transcription factor binding and thus contribute to disease.
One such binding site is within the promoter region of a gene called TRPM1, previously associated with AMD, and sequence variants at that site were found to alter the binding strength of LHX2. The so-called C version bound more strongly than the T version, and TRPM1 gene activity was higher when the C allele was present instead of the T allele.
The results of this study indicate that the previously known increased risk of AMD by the GWAS-identified variants is due to reduced binding of the LHX2 transcription factor to the TRPM1 gene promoter, resulting in decreased activity of this gene. indicates a decline. This gene encodes a membrane ion channel, and previous studies have shown that mutations in the gene also cause visual impairment.
“Our study demonstrates how delineation of tissue-specific transcriptional regulators, their binding sites across the genome, and their downstream gene regulatory networks can provide insight into the pathology of complex diseases. It exemplifies what
This finding reveals a regulatory module consisting of LHX2 and OTX2 that controls the development and maintenance of the retinal pigment epithelium, a tissue critical to visual function. Genomic analysis further links genomic regions joined by two developmental factors to the genetics of common multifactorial blinding diseases. age-related macular degeneration (AMD)”.
Ruth Asery-Padan at Tel Aviv University
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Journal reference:
Cohen-Gulkar, M., and others. (2023) The LHX2-OTX2 transcriptional regulatory module controls retinal pigment epithelium differentiation and underlies the genetic risk of age-related macular degeneration. PLOSbiology. doi.org/10.1371/journal.pbio.3001924.
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