Have you ever thought about why every chromosome in our cells has two copies? During the breeding process, we obtain a copy from each of our parents. This means that we also obtained two copies or alleles of each gene from each chromosome or pair of parents.
Both alleles can produce messenger ribonucleic acid (mRNA), which is the formula required for mRNA to manufacture proteins and maintain cell operation. Scientists assume that each gene has two alleles, which are redundant systems built into cells. If a mutation occurs in an allele on one of the chromosomes or causes a decrease in mRNA production, the allele on the other chromosome will serve as a backup to accelerate the production of sufficient mRNA to compensate for the loss of the first allele. This redundancy enables us humans to largely resist the impact of implicit mutations.
However, there is a type of gene called haploinsufficiency gene that relies on the sustained expression of two intact alleles. If only one allele of a gene is damaged due to an insufficient single dose, it can lead to human diseases. Therefore, it is hypothesized that cells may have a special “safety” mechanism to protect the mRNA expression of these specific genes. A research team led by Asifa Akhtar, director of the Max Planck Institute for Immunobiology and Epigenetics in Germany, has discovered such a mechanism in a new study. The relevant research results were published in the Nature journal, under the title “MSL2 ensures biallelic gene expression in mammals”.
MSL2 is an epigenetic dose-sensing protein
These authors found that the epigenetic regulatory factor MSL2 can ensure the expression of two alleles of a specific single dose deficient gene, thereby ensuring the correct mRNA dose. This is crucial because the required dosage varies depending on the tissue in which the gene is expressed. They found for the first time that the MSL2 protein can perceive these dose-sensitive genes and ensure their biallelic gene expression in relevant tissues or developmental stages.
Akhtar said, “We have been wondering if the gene copy from the mother on the chromosome can communicate with the gene copy from the father on the chromosome. Our findings suggest that there is intrinsic communication between these two alleles, and we speculate that MSL2 ensures communication between the father and mother – at least molecular communication.”
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Using genetic techniques to track allele regulatory factors
These authors were fascinated by a mechanism they discovered to protect the expression of biallelic genes with insufficient single dose, and thus investigated how this MSL2 mechanism works at the molecular level. To solve this problem, they used a small trick.
The co-first author of the paper, Yidan Sun, explained the method of allele-specific gene expression analysis, saying, “We hybridized mouse strains that are geographically distant from each other. Through this hybrid mouse system, they can analyze the activity of individual alleles.”
She added, “Compared to the standard expression data analysis method of adding gene products from two alleles, this provides us with the resolution required to separately track the expression status of each allele.”
Expected to develop new disease treatment strategies in the future
Their experiment confirmed that when MSL2 is missing in hybrid mouse cells, certain single-dose deficient genes can only achieve single allele gene expression. This means that in mammalian cells, MSL2 is necessary for the expression of double allelic genes with an insufficient single dose, which ensures gene function and the overall health of the organism. Interestingly, many single-dose deficient genes regulated by MSL2 are associated with neurological diseases.
The co-first author of the paper, Meike Wiese, said, “However, the tissue and cell type specificity of these genes adds fascinating color to this discovery. From the overall perspective of the organism, it raises the question of whether this backup system, coordinated by epigenetic factors such as MSL2, can explain why people, even with similar lifelong habits such as smoking or diet, have different health outcomes or disease risks.”
An Evolutionary Conservative Mechanism for Regulating Gene Dose
Akhtar said, my laboratory initially studied the dose compensation of fruit flies, which is the process by which male fruit flies with one X chromosome can obtain gene products at the same level as female fruit flies with two X chromosomes. For many years, we have been fascinated by how male fruit flies with only one X chromosome perform dual duties to produce the same mRNA compared to female fruit flies with two X chromosomes. If there is no such dual effect male fruit flies will die! Mammals seem to have cleverly employed this strategy. Our research findings clearly demonstrate how the same tools (such as MSL2) can be used again to regulate gene dosage during the evolutionary process. “Gene dosage is important, and our research has given us a new understanding of how cells in the body can ensure that we receive sufficient doses of mRNA.”
What truly excites these authors is that this discovery opens up new directions for a deeper understanding of the regulation of gene dosage within human cells. The revealed MSL2 may only be an example of such allele regulatory factors, indicating the existence of other factors that play similar roles. These new discoveries have profound implications for understanding diseases and have the potential to develop potential therapeutic methods.
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Reference
Yidan Sun et al. MSL2 ensures biallelic gene expression in mammals. Nature, 2023, doi:10.1038/s41586-023-06781-3.