Layers of gene control allow DNA to flexibly add new information. Genes and their genetic switches are organized into functional units to turn genes on or off as needed. Disrupting these units can lead to disease, but a new study makes it clear that they are more robust and flexible than previously thought. An international team of researchers found that a gene can still function even when new segments of DNA are introduced into the same genomic organizational unit.
Two meters of DNA is put into the tiny nucleus of every human cell. To provide the cell with the right information at the right time, the DNA molecule is efficiently packaged and bundled into functional units. Genes usually assemble with their control sequences to build physically separate workspaces. But what happens if these units become disrupted during evolution – or in an individual patient’s genome?
“Some of the genomic rearrangements we see in the clinic cause disease, while others don’t,” said Stefan Mundlos of Charité-Universitätsmedizin Berlin and head of the Development & Disease Research Group at the Max Planck Institute for Molecular Genetics (MPIMG) . “We still don’t fully understand why this is the case.”
In fact, many parts of the genome contain regulatory conflicts. A new study published in the journal Cell gives the first hints on how to solve them. Mundlos’ team of researchers studied an example where a new gene has been successfully integrated into the genome without disrupting the pre-existing control mechanisms of neighboring genes. The team also hoped to be able to draw conclusions about similar conditions in the cells of patients.
The researchers examined a mutation that occurred in the ancestor of all placental mammals, a group that includes humans but not marsupials like the opossum. The mutation brought the new gene Zfp42 into the workspace of the important developmental gene Fat1, a gene involved in the growth and migration of cells.
“We found that cells deal with the unwanted host with two separate mechanisms, depending on the situation in which the genes are needed,” said Michael Robson, who led the project. “In certain tissues, the new gene is epigenetically silenced and completely knocked out. However, during early embryonic development, both genes are active and the cell converts this part of the genome into new functional units that allow individual control.”
A newcomer to the workshop
Robson, his Ph.D. student Alessa Ringel and their colleagues examined Fat1’s organizational workspace. Like many other genes, it is instructed to turn on at specific times and places by other DNA sequences called enhancers. To allow enhancers and genes to communicate, DNA then folds and bends to bring them together in a sheltered workspace. These functional units of DNA are called topologically associated domains (TADs).
In chickens or opossums, only the Fat1 gene is in the same TAD as its enhancers. When the researcher used the “Hi-C” technique to see which parts of the DNA touched most often, the gene and its enhancer behaved as expected. In these animals, the DNA appeared to coil into a single ball, allowing both genetic sequences to mix, activating Fat1.
“But in placental mammals like mice or humans, it’s a little more complicated,” explains Ringel, the paper’s lead author. Right in between the Fat1 gene and its enhancer, there is this new gene called Zfp42. The same enhancer should control both genes, but this is not the case. “Both genes seem to get along just fine — they behave completely independently and become active in different tissues at different times of development.”
Go to sleep or rebuild your workspace
To answer the question of how the genes manage to avoid each other, the researchers compared cells from different mouse tissues: the developing embryonic limb and embryonic stem cells.
From these studies, the researchers learned that in embryonic limbs, the enhancer does indeed make contact with both genes, but Zfp42 remains inactive. It turns out that the newcomer is still in the same workspace but quietly sleeping in a corner. The gene had been silenced by DNA methylation, a chemical modification that locks genes in an off-state. But to put the Zfp42 gene to sleep, it has to be in exactly the right place. As soon as the researchers experimentally cut and paste it a bit to both sides, it was activated by Fat1’s amplifier.
The scientists were surprised to find that in the cells of the mouse embryonic stem cells, the DNA around the two genes is organized very differently. Zfp42 and Fat1 are now building their own physically separate workspaces with their own respective amplifiers.
The original TAD splits into smaller DNA blobs to separate the two genes. This was evident not only from Hi-C experiments that mapped the contact points between DNA segments, but also from high-resolution microscopic imaging and computer modeling that showed that each gene set up its own small workspace.
A robust and flexible system of genetic control
These two new mechanisms reveal how a single DNA “workspace” can be easily modified to host entirely different gene activities. “It’s fascinating to study how different layers of gene control complement each other,” Ringel says. “We have been surprised by the flexibility of our genomes to adapt and control genes in different situations. For example, our results show that TADs can have dynamic rather than static DNA structures.”
The TAD of the Fat1 gene has been stably maintained over hundreds of millions of years from evolution from fish and frogs to marsupials, adds project leader Robson. “TAD workspaces seem vulnerable at first because so much can go wrong if they’re disturbed,” he says. “But new genes have to go somewhere and we show how evolution can effectively alter regulatory domains to safely add new genes and functions.”
“Interestingly, this evolutionary setting is reflective of what we often see in patients with extreme genome changes like chromothripsis,” Mundlos says. “These patients may have shattered chromosomes but still have relatively mild symptoms. This could be explained by these additional regulatory mechanisms that offset deleterious effects by using the tools available to the genome.”
Exploring molecular boundaries in DNA
Michael I. Robson, Repression and 3D restructuring resolves regulatory conflicts in evolutionarily rearranged genomes, Cell (2022). DOI: 10.116/j.cell.2022.09.006. www.cell.com/cell/fulltext/S0092-8674(22)01128-X
Quote: How genes share their workspace (2022, October 5) retrieved October 5, 2022 from https://phys.org/news/2022-10-genes-workspace.html
This document is copyrighted. Other than fair dealing for personal study or research, nothing may be reproduced without written permission. The content is provided for informational purposes only.