Many proteins are adorned with carbohydrate chains called glycans that can dramatically alter their stability, localization or function. These diverse sugars are assembled and modified by a variety of glycosylating enzymes, with some glycans exclusively manufactured within specific organs or tissues.
Figure 1: Neural cell-specific modifications to chromosomal proteins govern the production of Gnt-IX and thereby ensure that branched O-mannose glycan production is restricted to these cells.
Copyright : 2011 iStockphoto/sitox
The â1,6-branched O-mannosyl glycan appears only in the mammalian brain. Naoyuki Taniguchi’s team at the RIKEN Advanced Science Institute in Wako recently characterized the enzyme, N-acetylglucosaminyltransferase IX (GnT-IX, also called GnT-Vb) that produces this particular glycan variant1 (Fig. 1). “We knew that some glycan-synthesizing enzymes are expressed in restricted tissues, but did not know how they are expressed,” says Yasuhiko Kizuka, a researcher in Taniguchi’s laboratory. “This led us to investigate how GnT-IX is specifically expressed in the brain.”
Many genes are regulated by so-called ‘epigenetic mechanisms’, in which gene expression is modulated via modification of the histone protein scaffold that supports chromosomal DNA, and the researchers began by examining this possibility. When histone proteins undergo a modification known as acetylation, nearby genes are typically activated; conversely, removal of this acetylation has an inhibitory effect.
Taniguchi and colleagues determined that the gene encoding GnT-IX is typically maintained in an inactive, non-acetylated state in 3T3-L1, a cell line derived from the fibroblasts that form connective tissue. However, when the researchers treated these cells with a drug that promotes histone acetylation, they strongly expressed GnT-IX. The brain tumor-derived Neuro2A cell line, however, naturally expresses high levels of GnT-IX. The researchers found that these cells normally maintain the chromatin near this gene in a state that stimulates activation.
In subsequent experiments, Kizuka and Taniguchi not only identified specific DNA sequences that directly regulate GnT-IX activity, but also two proteins that bind to these sites to drive expression. They found one of these factors, CTCF, in both 3T3-L1 and Neuro2A cells, but its recruitment to the GnT-IX gene was far stronger under the favorable histone modification conditions found in the latter cells.
Intriguingly, a preliminary screen of four other glycosylation enzymes suggested that similar mechanisms govern their tissue-specificity. “Our work suggests that expression of many other glyco-genes could be regulated epigenetically,” says Kizuka.
In future studies, the researchers intend to explore how this regulatory mechanism plays into the bigger picture of glycan function. “Our group has been trying to elucidate the ‘glycan cycle’—how glycans are dynamically synthesized, play diverse roles and are degraded—using a systems biology approach,” says Kizuka. “This work tells us that epigenetic regulation is a part of this cycle.”
The corresponding author for this highlight is based at the System Glycobiology Research Group, RIKEN Advanced Science Institute
Mass spectrometry sheds new light on thallium poisoning cold case
14.12.2018 | University of Maryland
Protein involved in nematode stress response identified
14.12.2018 | University of Illinois College of Agricultural, Consumer and Environmental Sciences
The more objects we make "smart," from watches to entire buildings, the greater the need for these devices to store and retrieve massive amounts of data quickly without consuming too much power.
Millions of new memory cells could be part of a computer chip and provide that speed and energy savings, thanks to the discovery of a previously unobserved...
What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...
A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.
The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...
A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.
Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...
Over the last decade, there has been much excitement about the discovery, recognised by the Nobel Prize in Physics only two years ago, that there are two types...
12.12.2018 | Event News
10.12.2018 | Event News
06.12.2018 | Event News
14.12.2018 | Power and Electrical Engineering
14.12.2018 | Physics and Astronomy
14.12.2018 | Physics and Astronomy