Protein glycosylation plays a major role in DNA methylation

An underlying principle in molecular biology is that “DNA makes RNA makes protein.” The process of gene expression, such as producing RNA from a particular DNA sequence, is firmly controlled in various ways.

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As such, the DNA carries a reversible chemical modification—known as methylation—that can affect the expression of genes.

Researchers from European Molecular Biology Laboratory, Rome (EMBL Rome), in association with Tim Bestor from New York-based Columbia University and John Edwards from Washington University in St. Louis, Missouri, have now demonstrated for the first time how cells are instructed by DNA methylation to repress parts of their genome by causing the assembly of a silencing complex.

The researchers’ study was published in the Proceedings of the National Academy of Sciences (PNAS) journal.

DNA methylation is the sole epigenetic modification known to be inherited following cell division, which means as soon as a particular sequence is methylated, it continues to remain in that state all through the lifespan of an organism.

Methylation serves as a mark on the DNA that deactivates certain genes in a way that relies on the parental origin. In addition, DNA methylation serves as a cellular defense mechanism against parasitic parts of DNA that can shift inside the genome and threaten its integrity. Cells are instructed by the modification to repress these supposed transposons.

In spite of 40 years of research, the accurate mechanism through which gene expression is repressed by DNA methylation has remained elusive.

The researchers in Mathieu Boulard’s team identified that the protein TRIM28, which is a known silencing factor that had not been associated earlier with DNA methylation, is needed for the repression of methylated genes. But the TRIM28 protein does not directly communicate with the DNA, which meant that other kinds of proteins must also be involved in the process.

Through a combination of biochemical and genetic analyses, the researchers demonstrated that in the presence of DNA methylation, the TRIM28 protein adheres to the OGT enzyme, which alters other proteins by introducing sugar groups (a process called glycosylation).

They also demonstrated that methylation-directed glycosylation of certain DNA binding proteins inhibits methylated genes from being expressed.

Our study reveals that protein glycosylation plays a central role in DNA methylation, thereby unveiling the mechanism behind the most studied epigenetic modification.”

Matthieu Boulard, Group Leader, European Molecular Biology Laboratory, Rome

The initial proof that glycosylation plays a crucial function in gene regulation emerged from another study performed at EMBL, which revealed that glycosylation suppresses developmental genes in specific cells during the development of the fruit fly Drosophila. But in this case, DNA methylation is not involved in gene repression.

We show that DNA methylation in mammals induces gene silencing by activating a process that induces glycosylation of regulatory factors. These findings address one of the core questions in the field of epigenetics, which is the nature of the mechanism that represses methylated promoters.”

Matthieu Boulard, Group Leader, European Molecular Biology Laboratory, Rome