The proteins struggle to find their binding sites when DNA sequences vary
At Tel Aviv University, researchers have traced a hidden thread in the human genome — one that may help explain why some people lose their sight as they age. By identifying two proteins that govern gene expression in the retinal tissue first claimed by macular degeneration, and mapping precisely where those proteins bind to DNA, scientists have illuminated a class of genetic risk that had long resisted understanding. The discovery belongs to a broader reckoning in medicine: that the spaces between our genes, long dismissed as silent, may carry some of the most consequential instructions of all.
- Age-related macular degeneration quietly steals independence from millions of elderly people in developed countries, yet its genetic origins have remained stubbornly obscure.
- The tension lies in a fundamental puzzle — genome-wide studies kept pointing to regions between genes as risk zones, but no one could explain what those dark stretches were actually doing.
- Tel Aviv researchers zeroed in on the retinal pigmented epithelium, the tissue that fails first in AMD, and identified two master-switch proteins — LHX2 and OTX2 — that control its entire genetic program.
- Using ChIP-seq technology, they mapped the exact DNA binding sites of both proteins and found them clustered precisely in regions already flagged as AMD risk zones — the missing link between variation and disease.
- When natural DNA sequence differences prevent these proteins from binding correctly, a cascade follows: a critical ion channel gene goes quiet, and the tissue's resilience begins to erode.
- The methodology now offers a replicable path into other complex diseases — diabetes, mental illness, inflammatory conditions — where genomic risk has been sensed but never fully decoded.
Scientists at Tel Aviv University have identified a new genetic risk factor for age-related macular degeneration, the leading cause of vision loss in older adults across developed countries — and in doing so, they've shed light on a class of genomic mystery that has long frustrated researchers.
Most serious diseases don't arise from a single faulty gene. AMD is no exception. Earlier genome-wide studies had already flagged several regions of DNA as statistically linked to the disease, but those regions fell between genes, in territory whose function was poorly understood. Professors Ruth Ashery-Padan and Ran Elkon set out to understand what was actually happening in those spaces.
Their focus was the retinal pigmented epithelium — a thin tissue beneath the retina's light-sensitive cells that deteriorates early in AMD. Through experiments in mice and human cells, they identified two proteins, LHX2 and OTX2, that act as master regulators of gene expression in this tissue, binding to DNA and determining which genes are switched on or off.
Using ChIP-seq technology to map the precise locations where these proteins attach to DNA, the team made a decisive discovery: the binding sites clustered in the very genomic regions previously associated with AMD risk. When natural DNA variations alter those sites, the proteins can't bind properly — and the genes they're meant to activate, including one coding for an ion channel essential to eye function, fall silent. That cascade of reduced activity raises the likelihood that AMD will take hold.
Published in PLOS Biology, the findings reframe how genetic risk can be understood in complex diseases. The methodology the team developed could now be applied to diabetes, inflammatory bowel disease, and various mental illnesses — conditions where researchers have long known something in the genome matters, but couldn't say exactly what, or why.
Scientists at Tel Aviv University have identified a new genetic risk factor for age-related macular degeneration, the leading cause of vision loss in older adults across developed countries. The discovery marks the first time researchers have pinpointed the exact genomic locations where specific proteins operate in the tissue most vulnerable to the disease, and connected those locations to AMD risk.
The challenge that drove this work is fundamental to modern genetics: most serious diseases don't result from a single broken gene, but from a combination of genetic variations and environmental factors working together. AMD fits this pattern exactly. Researchers comparing the genomes of people with and without the disease had already found differences scattered across several genomic regions—stretches of DNA that seemed to matter but contained no obvious culprit. The regions lay between genes, in territory whose function remained largely mysterious. The Tel Aviv team, led by Prof. Ruth Ashery-Padan and Prof. Ran Elkon, decided to focus on understanding what was actually happening in those shadowy spaces.
They began by studying the retinal pigmented epithelium, a thin layer of tissue that sits beneath the light-sensitive cells of the retina and keeps them alive. This tissue deteriorates early in AMD, making it the logical place to look. Through a series of experiments in mice and human cells, the researchers identified two proteins—LHX2 and OTX2—that act as master switches for gene expression in this tissue. These proteins bind to specific sites on the DNA and essentially tell the cell which genes to turn on or off, controlling the entire genetic program that keeps the tissue functioning.
The next step required mapping exactly where these proteins bind. Using a technique called ChIP-seq, which identifies the precise locations where proteins attach to DNA, the researchers made a striking discovery: the binding sites for both proteins clustered together in a region that had already been flagged in earlier studies as connected to AMD risk. This was the missing link. When DNA sequences in these regions vary—as they do naturally between individuals—the proteins struggle to find and attach to their binding sites. When the proteins can't bind properly, they can't activate the genes they're supposed to regulate, including one that codes for an ion channel critical to eye function. The resulting decrease in gene activity ripples through the entire tissue, raising the risk that AMD will develop.
The work, published in PLOS Biology, opens a new way of thinking about genetic disease. For decades, researchers have focused on genes themselves—the stretches of DNA that code for proteins. But the regions between genes, once dismissed as junk, clearly play a crucial role in determining whether disease develops. The methodology the Tel Aviv team developed could be applied to other complex diseases shaped by multiple genetic factors: diabetes, inflammatory bowel disease, various forms of mental illness. Each of these conditions has left researchers staring at genomic regions they knew mattered but couldn't explain. Now there's a path forward—a way to move from knowing something is wrong to understanding exactly what it is.
Citas Notables
Our findings provide new insight into a previously unsolved issue: the functions and mode of operation of genomic sequences located outside the genes, and how they are involved in complex genetic diseases.— Prof. Ruth Ashery-Padan, Tel Aviv University
We assume that due to changes in DNA sequences in these genomic regions, transcriptional proteins cannot easily find and bind with their binding sites, reducing the expression of nearby genes and increasing AMD risk.— Prof. Ran Elkon, Tel Aviv University
La Conversación del Hearth Otra perspectiva de la historia
Why does it matter that these proteins bind so close together in the genome?
Because it creates a single point of vulnerability. If variations in the DNA sequence disrupt both binding sites at once, you've knocked out the entire regulatory system for that region. It's like having two keys to the same lock—if the lock changes shape, both keys fail simultaneously.
But people with these genetic variations don't all get AMD. What else has to happen?
That's the complexity of the disease. The genetic variation loads the gun, but environment pulls the trigger. Age, smoking, diet, sun exposure—these all matter. The proteins we identified increase risk, they don't guarantee disease.
How does this change treatment?
Not immediately. But understanding the mechanism opens doors. If you know which genes aren't being expressed properly, you can think about ways to restore their expression, or compensate for what's missing. Right now, AMD treatments are limited. This gives researchers a target.
Why study the retinal pigmented epithelium specifically?
Because it's the first domino to fall. AMD starts there, in that supporting tissue. If you want to understand how the disease begins, you have to look at where it begins.
What surprised you most about the findings?
That the answer was hiding in plain sight. Researchers had already identified these genomic regions as important. We just had to ask the right question: what proteins are actually working there, and how do they work? The technology existed. We just needed to apply it carefully.