Clever Dosage Control Mechanism of Biallelic Genes
Published:06 Feb.2024    Source:Max Planck Institute of Immunobiology and Epigenetics
Researchers have uncovered a mechanism that safeguards the biallelic expression of haploinsufficient genes, shedding light on the importance of having two copies of each chromosome. A study by the lab of Asifa Akhtar identified the epigenetic regulator MSL2 an "anti-monoallelic" factor that maintains biallelic gene dosage. During reproduction, we receive one copy of each chromosome from each of our parents. This means that we also receive two copies, or alleles, of each gene -- one allele per chromosome or parent. Both alleles are able to produce messenger RNA, which is the recipe needed to make proteins and keep cells running.
Scientists hypothesize that having two alleles for each gene is the cell's in-built redundancy system. If there is ever a mutation or drop in messenger RNA production from the allele carried on one of the chromosomes, the allele on the second chromosome will serve as a backup and will be able to step up to produce sufficient messenger RNA output to compensate for loss of the first allele. This redundancy enables us as humans to be largely resistant to the effects of recessive mutations. The researchers found that the epigenetic regulator MSL2 guarantees the expression of both alleles of specific haploinsufficient genes, ensuring the right messenger RNA dosage. This is crucial because genes require different dosage depending on the tissues they are expressed in. With MSL2, the team has identified, for the first time, a protein that can sense these dosage-sensitive genes and ensure their biallelic expression in the relevant tissue or developmental stage. Fascinated by their discovery of a mechanism which safeguards the biallelic expression of haploinsufficient genes, the researchers investigated how this MSL2 mechanism works at the molecular level.
Their experiments demonstrated that when MSL2 was lost in hybrid mouse cells, certain haploinsufficient genes could only achieve monoallelic expression. This implies that in mammalian cells, MSL2 is necessary for the biallelic expression of genes, ensuring their functionality and, consequently, the overall health of the organism. Our results clearly illustrate how the same tools, like MSL2, are again used in evolution to regulate dosage of genes. Gene dosage matters, and our study provides a new level of understanding of how the cells in our body ensure that we get the right dose of messenger RNAs," says Asifa Akhtar. What truly excites the scientists is that this discovery opens new directions to delve deeper into understanding the modulation of gene dosage within our cells. MSL2, as revealed, may just be one example of such an allelic regulator, suggesting the existence of other factors performing similar roles.