Processes of parental-specific genetic activation have been unravelled.

Genomic imprinting, a process in which only the maternally or paternally inherited gene is active, may be linked to hereditary illnesses, malignancies, and cardiovascular problems. Scientists from the Technical University of Munich (TUM), the Max Planck Institute for Molecular Genetics (MPIMG) in Berlin, and Harvard University in Cambridge, Massachusetts (USA) have now explored the mechanisms that cause the genes to be deactivated.

Our cells include all of our mother's and father's genetic information. We inherit 23 chromosomes from each of them, which carry our DNA. As a result, our genome contains two copies of each gene, both of which are active in most cases. This has the advantage of generally cancelling out faulty mutations acquired from the mother or father by the other copy of the gene.

Only the gene acquired from the father or mother is active in about 1% of our genes, while the other is deactivated, a phenomenon known as genomic imprinting.

Methodology for treating disorders

"Many genetic and epigenetic illnesses, like as Beckwith-Wiedemann syndrome, Angelman syndrome, and Prader-Willi syndrome, are connected with genomic imprinting," says Dr. Daniel Andergassen, chairman of the Independent Junior Research Group at TUM's Institute of Pharmacology and Toxicology. "It would hypothetically be feasible to compensate for issues produced by the active, malfunctioning gene if the healthy, inactive gene could be reactivated."

"However, before we can design future treatments, we need to understand the principles," adds MPIMG director Prof. Alexander Meissner. "In recent years, it has become obvious that genomic imprinting is mediated by a variety of molecular processes."

The gene has a read lock.

In genomic imprinting, either the genetic material's "packaging" or the DNA itself is chemically altered. Instead of changing the genetic code, the alterations prevent the gene from being read.

"These are epigenetic pathways," Andergassen explains. "You may think of DNA as the hardware, and epigenetics as the software that controls the genes." Every cell in the body is involved in genetic control. Although all cells carry the same genetic information, various genes are active depending on the organ.

The "off switch" is removed with genetic scissors.

Meissner and Andergassen, who were still conducting research at Harvard University (USA) with Dr. Zachary Smith at the time of the study, utilised mice to investigate whether epigenetic pathways were responsible for imprinting.

They employed CRISPR-Cas9, a molecular biology technology that acts like a "genetic scissors," deleting and inserting segments of DNA. The researchers tested if the silenced gene was revived after removing known epigenetic "off switches." They were able to correlate the most critical epigenetic "off switches" with imprinted genes using this method.

Genes are rendered dormant by hydrocarbon compounds.

The majority of the genes are inactivated as a result of DNA methylation, which involves the attachment of hydrocarbon molecules to the genetic material. Polycombs are a group of enzymes that mute another set of genes. An second mechanism is at work in the placenta: some genes are deactivated in this tissue by chemically altering the proteins that serve as a structural scaffold for the DNA.

The minor but critical difference

The researchers looked into another process in addition to genomic imprinting, which turns off particular genes. One chromosome is completely inactive relatively early in embryonic development in female cells, which, unlike male cells, have two X chromosomes. Almost all mammals, including humans, exhibit this trait.

"We observed that the enzyme PRC2 is critical for X chromosome inactivation, at least in the placenta," adds Andergassen. "The quiet X chromosome is triggered after we eliminate this enzyme." Because reactivation of the quiet gene could compensate for the faulty active gene, the findings could be relevant for X-chromosome-related disorders. Andergassen will investigate if heart problems are linked to epigenetics, particularly the inactive X chromosome in women, in a follow-up investigation at TUM. "Because our epigenetics alter as we age, it's possible that the X chromosome reactivates and the duplicate genetic activity has a negative impact," the researcher explains.

The team was able to provide an overview of the epigenetic mechanisms that sustain genomic imprinting as a result of their research. "The three known epigenetic processes can explain practically all parent-specific gene expression," adds Andergassen. "However, little is known about placental expression and whether it is the same in other animals. More research is needed to figure out how these mechanisms affect the development of the foetus."