In the wall of every artery live cells whose job is to contract and relax, keeping the vessel in tone. But sometimes they forget their profession and start behaving like bone builders: they deposit calcium, turning an elastic tube into something brittle, rather like a shell. This process is called vascular calcification, and it kills quietly: in patients with kidney disease or atherosclerosis, calcium in the arteries raises the risk of death more strongly than cholesterol itself.
For a long time it was unclear which switch triggers this retraining. Now researchers have found the culprit: a protein complex called ncBAF, which works like a bookmark in a book, marking the pages of DNA that the cell should read. It contains the protein BRD9, which recognizes special marks on the DNA packaging, and BRG1, which pushes that packaging apart so that genes become accessible. When a cell is forced to live in an environment rich in calcium and phosphate, BRD9 appears within 48 hours, long before the cell begins to deposit mineral.
But the complex does not act alone. It binds to the transcription factor ETS2, and together they turn on a whole network of inflammation and osteogenesis genes. The scientists tested this on human cells: if you switch off BRD9, BRG1, or ETS2, calcium stops being deposited. And if you switch off other proteins of the same family, mineralization, on the contrary, intensifies. So it is not any change that matters, but precisely the right combination.
In human atherosclerotic plaques, cells with active ETS2 and BRG1 sit next to macrophages, immune cells that arrive at the site of damage. Perhaps it is the macrophages that send the signal triggering the switch. The higher the level of ETS2 in an aortic sample, the stronger the calcification. This is no longer just a correlation in a test tube but a trace in real vessels.
Now doctors have a target: BRD9 inhibitors already exist and could slow calcification at an early stage, before irreversible deposits appear. And the level of ETS2 in a vessel biopsy could become a marker that warns of trouble in advance. The turncoat cell gives itself away long before it builds bone inside the artery.
The protein BRD9 is named after its bromodomain, a pocket that recognizes acetylated lysines on histones. The inhibitor I-BRD9 occupies this pocket like a key inserted into a lock, preventing the complex from landing on chromatin.
The idea of 'reprogramming' cells in an adult body recalls the plot of the movie Total Recall, where implanted memories change a person's identity. Here an epigenetic complex changes the cell's 'memory' of its profession, forcing a contractile cell to become a bone builder.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.