Painting genes with ubiquitin

Scientists led by Jürg Müller at the MPI of Biochemistry have deciphered a read-write mechanism that influences the expression of our genes.

Researchers at the Max Planck Institute (MPI) of Biochemistry have now elucidated a read-write mechanism by which histone H2A is marked with ubiquitin along genes. This tagging is a posttranslational modification, essentially a change to proteins that occurs after they are made. Especially on the histone proteins that package the DNA with our genetic information, such modifications can affect the expression of the underlying genes. The results of the study have been published in the journal Nature Structural and Molecular Biology.

The protein change under investigation is the labeling of nucleosomes, which are formed by DNA wound around a core of histone proteins, with ubiquitin. Rather than signaling protein degradation, the addition of a single ubiquitin molecule here triggers a series of chromatin remodeling processes that affect the accessibility of genetic information.

“Our lab is dedicated to unraveling the molecular mechanisms behind the regulation of chromatin structure in the cell nucleus. The basic building blocks of chromatin are nucleosomes, which consist of DNA wrapped around histones like a string of pearls. These structural units play a crucial role in the organization of our genetic material and many key steps within this organization occur through posttranslational modifications of specific sites on histones,” explains Maria Ciapponi, first author of the study.

The researchers had previously shown what happens to chromatin when ubiquitin is attached to the histone H2A. In their current study, they now focused on the question of how exactly this ubiquitin tag is added along a gene. They discovered that the Polycomb Repressive Complex 1, or PRC1, performs the tagging via a read-write mechanism. The “reader” side of the complex recognizes a nucleosome that already carries the ubiquitin tag and binds to it, simultaneously allowing the “writer” side of the complex to deposit ubiquitin on a neighboring unmodified nucleosome.

In essence, this process can be thought of as PRC1 acting as a paintbrush, spreading the “paint” ubiquitin further along a gene by anchoring to a colored nucleosome while painting on a neighboring still empty nucleosome.

“During the development of an organism, enzymes often need to add a specific tag to as many nucleosomes as possible across the underlying gene. They have to do this ‘painting’ of a gene with the tag rapidly, and they have to do it in the super-crowded environment of the nucleus where the enzymes encounter several million nucleosomes that are all built the same way,” explains Jürg Müller, corresponding author and head of the Chromatin Biology research group at the MPI of Biochemistry.

“Our current work and our previous study on another complex called PRC2, which adds a different tag, has allowed us to visualize at the atomic level how PRC1 and PRC2 add their tags along genes. In both cases they do so with the help of an already tagged nucleosome neighbor. However, not only the tag but also the mechanism by which these neighbors help to paint the gene is very different. In the future, this may make it possible to design drugs that specifically interfere with one or the other tagging system, since both are frequently mutated in cancers," concludes Müller further.

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Dictionary of the Research Group Chromatin Biology:

DNA: "DNA" stands for deoxyribonucleic acid and is the name for genetic information. DNA contains the "genetic code", in other words the blueprint of a living organism.

Nucleosome: The nucleosome is the complex that the DNA forms with histones and it is the basic structure unit of chromatin.

Gene expression: Gene expression describes the conversion of genetic material into a "usable form", such as RNA or proteins.

Chromatin: Chromatin is the material that makes up chromosomes. It contains our DNA, which is packaged around histones in cell nuclei.

Histone: Histones are spherical proteins.

Posttransaltional modifications: Posttranslational modifications are changes to proteins that occur after their production.

Ubiquitin: Ubiquitin is a small protein that is often attached to other proteins as a marker. This process is called ubiquitylation.