Glycans – the sweet difference

It's easy to forget that there's much more behind our individuality than genetics. A guest blog by Professor Vlatka Zoldos looks at the epigenetics of glycan protein modifications, and how this has been evolutionarily advantageous.

As we grow older, many of us get terrified how much we start to look like our parents. Genes seem to be unforgiving. We got them at the time of conception and they stay with us for the rest of our lives. Can we do anything to change the statement we don’t want to hear: “If you want to know what a girl will look like when she’s older, just look at her mother”? Maybe not in terms of physical appearance, but today we are aware that we are not determined only with our genes.

Excluding undesirable mutations, genes can be correctly maintained and regulated in response to the environment in order to keep physiological homeostasis. Epigenetics has for a while been established as a mediator between our genes and the environment. It comes naturally to ask the question: Can we use epigenetic regulation of our genes to improve our appearance, our health, and possibly to “change” our genetic heritage in a way that would bring a benefit for us as individuals, and perhaps for our descendants?

Many of us have failed to learn or have forgotten that the majority of all proteins, which evolved after the appearance of multicellular life, were modified by the addition of glycan molecules.”

It seems that we can. The cosmetic giant L’Oreal is currently advertising glycans as “the wonder ingredient you’ve never heard of that could make you look years younger”. Hard-core science has also recognized glycans as something valuable in research of cancer and other complex diseases. A recent comprehensive report endorsed by the US National Academies has stated that “glycans are directly involved in the pathophysiology of every major disease” and that “additional knowledge from glycoscience will be needed to realize the goals of personalized medicine and to take advantage of the substantial investments in human genome and proteome research and its impact on human health.

Even high-school kids know that proteins perform the majority of functions in a living cell and that the sequence of amino acids in a protein is determined by the sequence of nucleotides in the corresponding gene. But many of us have failed to learn or have forgotten that the majority of all proteins, which evolved after the appearance of multicellular life, were modified by the addition of glycan molecules. Within the complex glycoprotein molecule, the glycan part is responsible for a significant part of its structure and the function.

However, glycan structure is not determined with a single gene, but rather by a complex dynamic network of many genes. Single nucleotide polymorphisms in any of these genes may affect the final structure of a glycan consisting of several monosaccharides. Moreover, the network responsible for biosynthesis of glycans includes a number of small metabolites that are influenced by various environmental factors. Therefore glycans are not defined simply by a genetic script, but also by various environmental factors that could either be currently present in the environment, or acted sometime in our early environment (during intrauterine development) and left marks in the epigenetic memory.

Why are glycans so important? For instance, they provide a eukaryotic organism with a strategy to compete with bacterial and viral pathogens. Bacteria and viruses produce a large number of slightly different offspring in only several hours. Those slight differences arise as a result of mutations in their genetic material and represent a potential for adaptation. Prokaryotes thus seem to outcompete eukaryotic host organisms in their never-ending struggle for survival.

Eukaryotic organisms cannot afford such an expensive strategy due to their longer and more complex life cycles. Instead, they evolved sophisticated mechanisms in order to preserve a small number of highly valuable individuals, which is even more pronounced in high-density populations such as the human population. The mammalian immune system is often not efficient enough to mount an immediate counterattack against novel pathogens. The molecules at the surface of a pathogen represent its “face” by which it is recognized by the immune system. Any variation in the pathogen’s surface could make it resistant to our preexisting immunity.

On the other hand, successful infection requires specific recognition of certain features on the surface molecules of the host organism, and one of the mechanisms that higher organisms use to limit transmission of pathogens is the presentation of different structures on their cell surface. This is mostly achieved by variation in cell surface glycoconjugates, and an excellent example is the ABO blood group system.

Variation in sugars and epigenetic regulation … play a role in one of the most prevalent diseases of modern society – inflammatory bowel disease.”

The epigenetic modification of glyco-genes, i.e. the genes involved in the synthesis of glycans, offers a way of creating new complex structural features which could evade recognition by a specific virus or bacteria and thus make the organism resistant to infection by these pathogens. Instead of waiting for generations for a mutation to occur, adaptation by tuning gene expression and thus surface presentation, largely by means of epigenetically controlled changes in glycosylation pattern, could provide higher eukaryotes with a powerful way of competing with microorganisms, giving them the edge in the constant struggle for survival.

An example is the symbiotic relationship between humans and intestinal bacteria. While the intestinal bacteria help us in food digestion and protection against pathogenic bacteria, they use our glycans as receptors for colonization of the intestine. Variation in sugars and epigenetic regulation of this variation play a role in one of the most prevalent diseases of modern society – inflammatory bowel disease.

One of the biological dogmas is that self-replicating nucleic acids (the first revolution in evolution) provided the basis for development of early life through translation of nucleotide sequence into a sequence of amino acids to create the main effectors of life at the cellular level – the proteins (the second revolution in evolution). The integration of different cells into a complex multicellular organism required additional layers of complexity and the invention of glycans (the third revolution in evolution) through its inherent ability to create novel structures without the need to mutate the genetic information, but to alter it by epigenetic modifications instead, thus providing multicellular organisms with a mechanism to compensate for their longer generation time by using their higher complexity for rapid adaptation to various environmental challenges.

The greatest evolutionary advantage that glycans confer to higher eukaryotes is the ability to create new structures without introducing changes into the precious genetic heritage. Glycans contribute up to 50% of the total protein mass and even more to the molecular volume of many proteins. Thus, a large part of glycoproteins is not directly hardwired in the genome but is rather a platform for rapid and extensive epiproteomic adaptation.

Vlatka Zoldos

Vlatka Zoldos is a Professor of Genetics and Epigenetics at the University of Zagreb, Croatia. Her research focuses on the epigenetics of protein glycosylation, and she is a member of the Clinical Epigenetics Editorial Board.

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