How Epigenetics Can Restrict Parent-Specific Gene Information

Children are a blend of both their parent’s genes, but not necessarily in an equal way. Some genes inherited from either the father or mother are epigenetically marked with information that causes them to be inactive. This phenomenon is known as genomic imprinting and, although normal, could lead to disease if combined with mutations.

For the most part, we acquire two working copies of each gene – one from our dad and one from our mom. Although in genomic imprinting, one of the two copies is silenced by an epigenetic mechanism. How this event occurs at a single position on the DNA or across chromosomes is not fully understood.

Now, researchers from Germany and the US have investigated the mechanisms liable for deactivating parent-specific genes. Reported in Developmental Cell earlier this year, their analysis identified three distinct mechanisms responsible for genomic imprinting, including DNA methylation, polycomb-based repression, and histone 3 lysine 9 methylation (H3K9me).

Although very few genes are imprinted, disruptions in the process can cause gene copies to be both active or inactive, leading to severe developmental disorders and certain cancers. Known diseases associated with genomic imprinting include Beckwith-Wiedemann syndrome, Angelman syndrome, Prader-Willi syndrome, and Wilm’s tumor.

For these types of diseases, some of the genes are erroneously silenced in the same chromosome region for the egg and the sperm. “If the healthy, deactivated gene could be reactivated, it would be theoretically possible to compensate for complications caused by the active, defective gene,” says Dr. Daniel Andergassen, author and researcher at Technical University of Munich (TUM).

However, before future treatments can be developed, Prof. Alexander Meissner, director at the Max Planck Institute for Molecular Genetics explains that it’s necessary to understand the fundamentals of genomic imprinting. “It has become clear in recent years that genomic imprinting is mediated by multiple molecular mechanisms,” says Meissne.

Genomic imprinting is an epigenetic process and, unlike genetic mutations, does not alter the DNA code itself. Instead, it influences gene expression by chemically modifying the DNA and/or the structure of the chromatin molecule. Often, the modifications blocks gene information from being transmitted from one parent (or sometimes both) to the germ cell; thus, affecting the development of the next generation.

For many years, DNA methylation was thought to be the only epigenetic modification that could affect the transmission from the germline into offspring. The team here found that while most genes are silenced by DNA methylation, a lesser amount can be inactivated by a group of enzymes called Polycombs. Additionally, histone proteins, namely H3K27me3, can functionally deactivate specific genes after implantation in the placental tissue.

The researchers conducted their study on mice and used a newer technique called CRISPR-Cas9 – a very effective genome editing tool that can precisely remove segments of DNA. The CRISPR tool allowed them to selectively delete known epigenetic regulators. Then they observed which “shut off” genes were reactivated, allowing them to identify the epigenetic mechanism associated with the imprinted genes.

In addition, the researchers also investigated the double X chromosome that female cells carry. While males have one X and one Y chromosome, females have two X chromosomes. However, one of the X’s is silenced very early in embryonic development. This phenomenon is called X-inactivation, and it occurs in nearly all mammals.

Interestingly, Andergassen and his team found that the Polycomb Repressive Complex 2 (PRC2) enzyme plays an essential role in the inactivation of the X chromosome in the placenta. “Once we remove this enzyme, the silent X chromosome is reactivated,” says Andergassen. This new evidence could be helpful in developing therapies for diseases related to the X chromosome. According to the researcher, if the “turned off” gene can be reactivated, it might be able to remedy the defective “turned on” gene.

Andergassen plans to explore this further in regards to heart disease. He says, “Because our epigenetics change as we get old, it is conceivable that the X chromosome becomes active again and that the duplicate genetic activity has a negative influence.”

Overall, this study provides a comprehensive inventory of the epigenetic mechanisms involved in maintaining genomic imprinting. “We can explain virtually all parent-specific gene expression with the three known epigenetic mechanisms,” says Andergassen. Further studies are needed to investigate the expression in the placenta and how these processes affect the developing fetus.

Source: D Andergassenet et al. (2021) Diverse epigenetic mechanisms maintain parental imprints within the embryonic and extraembryonic lineages. Developmental Cell, 2021.

Reference: Epigenetic mechanisms for parent-specific genetic activation decoded: Unmuting the genome. Technical University of Munich, January 12, 2022.