As part of the study, the Ashona researchers were able to identify proteins whose role is essential for the development and activity of the tissue affected by the disease, to precisely locate their location in genomic regions outside of the genes, and to identify the relationship between the changes in these regions and the risk of developing AMD
Researchers from Tel Aviv University have identified a new genetic risk factor for the complex eye disease AMD, which is a leading cause of vision loss in old age. As part of the study, the Ashona researchers were able to identify proteins whose role is essential for the development and activity of the tissue affected by the disease, to precisely locate their location in genomic regions outside of the genes, and to identify the relationship between the changes in these regions and the risk of developing AMD. According to the research team, the discovery deepens the understanding regarding the role of regions in the genome outside the genes, which until now have been a mystery. The new method may allow the deciphering of additional genetic mechanisms involved in a variety of complex genetic diseases.
Deciphering a combination of genetic and environmental factors
The research was conducted under the leadership of Prof. Ruth Ashari-Fedan and Prof. Rani Alkon from the Department of Human Molecular Genetics and Biochemistry at the Sackler Faculty of Medicine and Purple School of Neuroscience and the team of researchers in the laboratories led by Mazel Cohen Golkar, Naama Masika, Ahuvit David and Mai Eshel. The article was published in the journal PLOS Biology.
"One of the biggest challenges in genetics research today is deciphering genetic mechanisms that cause complex diseases, i.e. those that are not caused by a defect in a specific and identified gene, but by a combination of several genetic and environmental factors", explains Prof. Ashari-Feden and expands "It is a very wide variety of Diseases, including diabetes, intestinal diseases and mental illnesses of all kinds. In our research we focused on the eye disease AMD (Age-related Macular Degeneration), or by its Hebrew name 'age-related macular degeneration', in which the central area of the retina degenerates. The disease usually breaks out at an older age and is a leading cause of vision loss in the developed world."
“AMD has a significant genetic component. Studies that compared the genomes of sick and healthy people identified differences in several regions of the genome, which are apparently related to risk factors for the disease. However, the differences in the genome were not located within any specific gene, but in the extensive areas between the genes, whose role and mode of functioning are still unknown to science. A similar situation was discovered in a wide variety of other complex genetic diseases. In fact, the situation today is that comparative studies know how to identify entire regions in the genome that are apparently related to the disease, but it is very difficult to put one's finger on a certain characteristic in those regions, and define it as a risk factor. In our research, we sought to answer this issue," adds Prof. Alkon.
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The research focused on the cells of a tissue in the eye known as the pigment epithelium, which is a supporting tissue that supports the light receptors in the retina (photoreceptors), and is essential for their development and survival throughout life. According to the researchers, this tissue is already damaged in the first stages of the AMD disease.
"First, we wanted to understand the genetic mechanism that activates and controls the unique activity of the pigment epithelial cells. Through a series of experiments that included the elimination of various proteins in a mouse model and in human cells, we were able to identify two central proteins called LHX2 and OTX2, which together dictate the expression of many genes that are unique to this tissue. These are proteins of the 'transcription proteins' type, whose function is to bind to certain sites in the DNA of a cell, and in this way determine which genes will be expressed in that cell," explains Prof. Ashari-Fedan.
The next challenge was to map exactly where in the genome the two milk proteins are located. To this end, the researchers used the innovative technology called ChIP-seq, which is a sequencing method that enables the identification of binding sites where proteins bind to DNA. Prof. Elkon: "We found that the two proteins bind to sites adjacent to each other in the genome. Moreover, it turned out that these were sites in the genome that had previously been identified as being associated with risk factors for AMD (that is, sequences in which differences were found between healthy and diseased individuals). We hypothesize that following the changes in the DNA sequences in those regions, the transcription proteins find it difficult to recognize the binding sites on the surface of the genome and bind to them. As a result of this disruption, the expression of the nearby gene controlled by the transcription proteins decreases (it is known that the gene encodes an ion channel that is important for eye function). The decrease in gene activity damages the entire tissue, and thus the risk of developing the disease increases."
"In our study we identified two proteins associated with risk factors for the complex genetic eye disease AMD. We were also able to map the location of these proteins in the genome for the first time, and found that they operate in an area previously identified as being associated with the risk of contracting the disease. Our findings deepen our understanding of the role and function of genomic sequences located outside genes, which have been a mystery until now, and how they are involved in complex genetic diseases. We believe that the innovative research method that produced the success will allow in the future the identification and mapping of many more genetic mechanisms related to AMD and other complex genetic diseases", concludes Prof. Ashari-Fedan.
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