Historically, scientists believed methyl groups could only stick to a particular DNA sequence: a cytosine followed by a guanine, called CpG. But in recent years, they have been found on other sequences, and so-called non-CpG methylation has been found in stem cells, and in neurons in the brain.
Now, a team of researchers at Johns Hopkins has discovered that non-CpG methylation occurs later and more dynamically in neurons than previously appreciated, and that it acts as a system of gene regulation, which can be independent of traditional CpG methylation.
In a study described in the January 28 issue of Nature Neuroscience, the Hopkins team describes this new gene control mechanism and how it may contribute to Rett Syndrome, a nervous system disorder affecting mostly girls that causes problems with movement and communication.
The team, led by Hongjun Song, Ph.D., professor of neurology and director of Johns Hopkins Medicine's Institute for Cell Engineering's Stem Cell Program, had found non-CpG methylation prevalent in neurons, a finding that surprised them, since this wasn’t found in any other cells besides stem cells.
By looking at what genes were being transcribed in neurons, he and his colleagues found that, like the form of methylation scientists had seen in stem cells, non-CpG methylation stops genes from being expressed. They also mapped the genome to find where non-CpG methylation happens, and found that it carves out its own niche, and are distributed in regions without CpG methlyation. "That was the first hint that maybe it can function independently of CpG methylation," Song says.
The new kind of methylation also seems to operate under different rules. Scientists have long thought methylation was final. Once a cytosine gets a methyl stuck to it, so the story went, that gene is shut off forever. "This became dogma," Song says. "Once cells become the right type, they don't change their identity or DNA methylation."
But non-CpG methylation seems to happen later, when the neuron is mature—and even after conventional wisdom said it was irreversible. The researchers learned this from an experiment in which they knocked out in adult mice the enzymes that attach methyl groups to DNA. They found the neurons still had just as much CpG methylation, but the non-CpG methylation dropped off. This suggests that non-CpG methylation is an active process, Song says, with methyl groups continually being taken off and put back on, adding to evidence that non-CpG methylation may play more of a role in managing operations in mature cells.
The researchers also found a way that non-CpG methylation is similar to CpG methylation in one important way: it's read by MeCP2, an enzyme long identified as a player in methylation.
That's significant because a mutation in MeCP2 causes Rett Syndrome, and understanding DNA methylation is key to understanding this syndrome. The disorder occurs, Song says, when working copies of the gene for MeCP2 are silenced during development.
Other authors on the paper include Junjie Guo, Yijing Su, Joo Heon Shin, Jaehoon Shin, Bin Xie, Chun Zhong, Shaohui Hu, Heng Zhu, Yuan Gao and Guo-li Ming, all of Johns Hopkins University;Hongda Li and Qiang Chang of the University of Wisconsin-Madison; and Thuc Le and Guoping Fan of University of California Los Angeles.
This research was supported by the National Institute of Neurological Disorders and Stroke(NS047344, NS048271 and NS072924), National Institute of Environmental Health Sciences (ES021957), the National Institute of Mental Health (MH087874), National Institute of Child Health and Human Development (HD06918, HD064743 and HD066560), the Simons Foundation Autism Research Initiative, NARSAD, the Maryland Stem Cell Research Fund (MSCRF) and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.
Nature Neuroscience articleContact Information
Vanessa McMains | Newswise
More than just a mechanical barrier – epithelial cells actively combat the flu virus
04.05.2016 | Helmholtz-Zentrum für Infektionsforschung
Discovery of a fundamental limit to the evolution of the genetic code
03.05.2016 | Institute for Research in Biomedicine (IRB Barcelona)
Using an ultra fast-scanning atomic force microscope, a team of researchers from the University of Basel has filmed “living” nuclear pore complexes at work for the first time. Nuclear pores are molecular machines that control the traffic entering or exiting the cell nucleus. In their article published in Nature Nanotechnology, the researchers explain how the passage of unwanted molecules is prevented by rapidly moving molecular “tentacles” inside the pore.
Using high-speed AFM, Roderick Lim, Argovia Professor at the Biozentrum and the Swiss Nanoscience Institute of the University of Basel, has not only directly...
If a person pushes a broken-down car alone, there is a certain effect. If another person helps, the result is the sum of their efforts. If two micro-particles are pushing another microparticle, however, the resulting effect may not necessarily be the sum their efforts. A recent study published in Nature Communications, measured this odd effect that scientists call “many body.”
In the microscopic world, where the modern miniaturized machines at the new frontiers of technology operate, as long as we are in the presence of two...
Researchers from the Max Planck Institute Stuttgart have developed self-propelled tiny ‘microbots’ that can remove lead or organic pollution from contaminated water.
Working with colleagues in Barcelona and Singapore, Samuel Sánchez’s group used graphene oxide to make their microscale motors, which are able to adsorb lead...
Neutron scattering and computational modeling have revealed unique and unexpected behavior of water molecules under extreme confinement that is unmatched by any known gas, liquid or solid states.
In a paper published in Physical Review Letters, researchers at the Department of Energy's Oak Ridge National Laboratory describe a new tunneling state of...
Honeycomb structures as the basic building block for industrial applications presented using holo pyramid
Researchers of the Alfred Wegener Institute (AWI) will introduce their latest developments in the field of bionic lightweight design at Hannover Messe from 25...
27.04.2016 | Event News
15.04.2016 | Event News
12.04.2016 | Event News
04.05.2016 | Physics and Astronomy
04.05.2016 | Physics and Astronomy
04.05.2016 | Materials Sciences