Concepts of the control of loopholes in gene expression need to be re -examined

The buildings are considered to be the key to showing up as quickly as possible

MIT researchers found that chromatin spends most of its time in a looped state (intermediate). Fully built loops (right) are found only three to six percent of the time. Edited: MIT

In human chromosomes, DNA is covered by proteins to form a very long beaded chain. This “sale” is embedded in a number of loopholes, which are thought to help cells regulate gene expression and facilitate DNA repair, among other functions. A new study from MIT shows that these loops are much stronger and shorter than expected.

In the new study, the researchers were able to observe the movement of a single point of the genome in a living cell for about two hours. They found that this loop was fully looped only 3 to 6 percent of the time, with a loop duration of only about 10 to 30 minutes. Evidence suggests that scientists’ understanding of how the loops change suggests how they need to be repaired, the researchers said.

“There are a lot of school examples of these images of loopholes that govern these processes. What our new paper shows is that this image is not accurate,” said Anders Sejr Hansen, the Underwood -Prescott Career Development Assistant Professor of Biological Engineering at MIT. “We think the performance of these centers is much stronger.”

Hansen is one of the top authors of the new research, along with Leonid Mirny, a professor at MIT’s Institute for Medical Engineering and Science and Physics, and Christoph Zechner, a fellow leader at the Max Planck Institute of Molecular Cell Biology. and Genetics in Dresden, Germany, and the Center for Systems Biology Dresden. MIT postdoc Michele Gabriele, Harvard University Ph.D. Hugo Brandão, and MIT graduate Simon Grosse-Holz were the first authors of the paper, which stands today at Science.

Out of the loop

Using computer simulations and experimental data, scientists with Mirny’s team at MIT showed that loops in the genome are formed by a process called extrusion, in which the molecule is strengthened. the growth of large loopholes. The car stops each time it encounters a “rest mark” in the DNA. The car that releases these loops is a complex protein called cohesin, while CTCF -bound DNA is the signaling pathway. These cohesin-mediated portals were observed between CTCF sites in previous experiments.

However, such experiments only give a snapshot of time over time, without knowing how the loops change over time. In their latest research, the researchers have developed technologies that allow them to record CTCF DNA cells so that they can extract DNA loops over hours. They also created a new statistical model that can compare looping events from image data.

“This approach is important for us to separate the signal from the noise in our experimental data and to calculate the looping,” Zechner said. “We believe those pathways will become critical for biology as we continue to push the boundaries of knowledge with experiments.”

The researchers used their method to extract a trace of the genome in embryonic stem cells. “If we put our data into the context of a single cell division loop, which lasts about 12 hours, the fully filled loop is only about 20 to 45 minutes, and about 3 to 6 percent of the time, ”Grosse-Holz said. .

“If the loop is available for a short period of time of the phone cycle and it’s very short, we don’t have to think of this entire state as the primary editor of the show,” Hansen said. “We think we need new models for how the 3D modeling of the genome can handle gene expression, DNA repair, and other processes below.”

Although few loopholes were made, the researchers found that loopholes were destroyed about 92 percent of the time. These tiny loopholes are difficult to inspect with earlier methods of detecting loopholes in the genome.

“In this study, by combining our experimental data with polymer simulations, we were able to enumerate the adjacent parts of the states that were not removed, released, and fully assembled,” he said. Brandão.

“Because these relationships are so short -lived, but too often, the first methods aren’t able to fully capture their dynamics,” Gabriele says. “With our new technology, we can start to make changes across the entire state without being open.”

The researchers believe that these loopholes may play more important roles in gene regulation than full loopholes. DNA strands run with each other at the beginning of loops and collapse, and these connections can help regulators such as amplifiers and gene propagators identify each other.

“More than 90 percent of the time, there are some transient loopholes, and the important thing is to have those loopholes that are permanently closed,” Mirny said. “The extrusion process itself is probably more important than the whole extrusion process that only stands for a short period of time.”

More loopholes to learn

Because most loopholes in the genome are much weaker than what the researchers studied in this paper, they believe that many loopholes are shown to be transient. very. They now plan to use their new technology to teach some of those loopholes, different types of phones.

“There are about 10,000 of these loops, and we’ve looked at one,” Hansen said. “We have a lot of non -technical evidence that shows that the results can be simple, but we haven’t shown that. We’re using the technology platform that we’ve set up, which combines new types of experiments. and numerically, we can begin to approach the loopholes. in the genome. “

Researchers also plan to investigate the role of specific loops in disease. Many patients, including a neurodevelopmental disorder called FOXG1 syndrome, can be affected by faulty dynamic loops. The researchers are studying how the normal and mutated nature of the FOXG1 gene, as well as the cancer-causing gene MYC, is affected by genome loop formation.

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More information:
Michele Gabriele et al, Dynamics of CTCF and cohesin mediated chromatin looping reported by life-cell imaging, Science (2022). DOI: 10.1126 / science.abn6583.

Presented by Massachusetts Institute of Technology

Directions: Study finds that genome openings in cells are not as long: Concepts of the regulation of loops in gene expression (2022, April 14) Retrieved 15 April 2022 from https: // genome-loops-dont-cells-theories.html

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