Human FACT complex coordinates cohesin and transcription on chromatin
This study reveals that the histone chaperone FACT facilitates cohesin translocation along nucleosome-dense chromatin to promote efficient loop extrusion and maintain topologically associating domain boundaries, while preventing cohesin's aberrant accumulation in gene bodies that would otherwise suppress transcription.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer
Inside the nucleus of every human cell, the DNA is not a loose string but a tightly wound package. To fit two meters of genetic code into a space smaller than a grain of sand, the cell wraps the DNA around spool-like proteins called histones, forming a dense structure known as chromatin. This packaging is essential for protection, but it also creates a physical barrier. For the cell to read its genes and make proteins, it must temporarily unwrap these spools and move machinery along the DNA. At the same time, the cell needs to organize this long DNA strand into specific 3D shapes, folding it into loops and domains so that the right genes can talk to the right partners. Two major players manage this delicate balance: a molecular machine called cohesin, which acts like a ring that grabs the DNA and pulls it into loops, and a helper protein called FACT, which acts like a chaperone to help the reading machinery slide through the dense chromatin. For a long time, scientists knew these two systems were important, but they did not understand how they worked together to keep the genome organized and functional.
A team of researchers at the MRC Laboratory of Medical Sciences in London and institutions in Japan has now uncovered a direct link between these two systems. Using human cells grown in the laboratory, they discovered that the FACT complex does more than just help read genes; it is also essential for helping the cohesin ring move along the DNA. The researchers found that without FACT, cohesin gets stuck. Instead of traveling smoothly to form the necessary loops that organize the genome, it piles up in the wrong places, specifically within the active sections of genes where it should not be. This blockage not only ruins the 3D structure of the DNA but also physically jams the machinery trying to read the genes, causing a drop in the production of essential proteins.
To see this happen, the scientists used a precise tool to remove the FACT protein from human cells almost instantly. They had engineered the cells so that when a specific plant hormone, called auxin, was added, the FACT protein would be destroyed within thirty minutes. This allowed them to watch what happened in real time without the cell having time to adapt or compensate. First, they checked if the cohesin ring could still get onto the DNA. They found that it could; the initial loading of cohesin was unaffected. However, once on the DNA, the cohesin ring lost its ability to travel. In healthy cells, cohesin moves along the DNA strand, pulling it into loops until it hits a stop sign made of a protein called CTCF. In the cells without FACT, the cohesin failed to reach these stop signs. Instead of forming neat loops, the cohesin signal became weak and scattered, and the large-scale domains that organize the genome began to lose their sharp boundaries.
The researchers then looked closer at where the cohesin went when it could not move properly. They discovered that in the absence of FACT, the cohesin rings accumulated in the middle of active genes. Normally, the cell's reading machinery, known as RNA polymerase, moves along these genes to copy the DNA into RNA. As it moves, it pushes the cohesin rings ahead of it, helping to clear the path. But when FACT is missing, the chromatin becomes too dense and difficult to navigate. The cohesin rings get trapped in the gene bodies, unable to be pushed forward or to slide past the obstacles. This accumulation was not random; it happened most strongly in the genes that were being read the most vigorously. The more active a gene was, the more cohesin piled up inside it.
This pile-up had a direct and damaging consequence for the cell's ability to function. The researchers found that the genes where cohesin accumulated saw a sharp drop in their activity. The trapped cohesin rings acted as a physical roadblock, preventing the reading machinery from passing through. To prove that the cohesin itself was the cause of this shutdown, and not just the lack of FACT, the scientists performed a second experiment. They removed the cohesin rings from the cells that were already missing FACT. When they did this, the transcription of the genes recovered. This confirmed that the problem was not just the loss of the helper protein, but specifically the presence of the stuck cohesin rings blocking the way.
The study reveals a critical coordination mechanism in the cell. The FACT complex serves a dual purpose: it helps the reading machinery move through the dense chromatin, and in doing so, it clears the path for the cohesin rings to travel and build the genome's 3D structure. When FACT is present, the reading machinery pushes the cohesin along, allowing it to reach its destination and form the loops that organize the cell's genetic library. When FACT is absent, the reading machinery slows down, the cohesin gets stuck, and the genome's structure collapses. This work shows that the physical state of the chromatin fiber itself is a key regulator of how the genome is folded and how genes are expressed, linking the mechanics of DNA movement directly to the cell's ability to read its own instructions.
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