Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Loss of Epigenetic Regulators Causes Mental Retardation

12.01.2010
Developing neurons don’t just need the right genes to guide them as they grow, they need access to the right genes at the right times.

The improper functioning of one specific protein complex that normally suppresses gene activation is responsible for a mental retardation-like syndrome in mice, reports a team of scientists at The Rockefeller University.

New findings, published in recent issues of Neuron and Science, indicate that malfunction of this protein complex causes mental retardation in mice and humans and may even play a role in promoting susceptibility to drug addiction. The research also establishes the complex as a key regulator of neuronal transcriptional identity.

“This research is the result of a close collaboration between our group and that of Alexander Tarakhovsky at The Rockefeller University, which is focused on understanding the role of epigenetic mechanisms in brain function, such as learning and memory,” says senior co-author Paul Greengard, Vincent Astor Professor and head of the Laboratory of Molecular and Cellular Neuroscience. Greengard won the 2000 Nobel Prize in Physiology or Medicine for research into how neurons communicate.

“Our findings may facilitate the identification of mechanisms responsible for long term storage of environmental information in neurons as well as other cell types,” says senior co-author Tarakhovsky, Irene Diamond Professor and head of the Laboratory of Lymphocyte Signaling. “We now have an animal system which not only reproduces the human disease, but may also enable us to understand the underlying mechanisms.”

Although genes provide the fixed template that instructs our cells how to grow, increasing evidence suggests that gene activity is governed by a group of proteins known as histones. Histones are subjected to chemical modifications that can permit or prevent genes from becoming active. These modifications are established by specific enzymes that add well-defined chemical residues to the amino acids localized within the tails of the histone proteins. Histone modifications were first identified in the early 1960s by Rockefeller scientist Vincent Allfrey and his colleagues. During the past two decades, research by Rockefeller University’s David Allis suggested that histone modification could generate a unique epigenetic “code” that regulates the specific recruitment of gene expression activators and repressors to individual genes.

The research program of the Greengard and Tarakhovsky labs focuses on GLP/G9a, an enzyme pair responsible for inducing an epigenetic mark widely known to silence gene expression in mammals, including humans. By attaching two methyl chemical groups to a specific amino acid on a specific histone, GLP/G9a suppresses gene activity. Tarakhovsky and his colleagues, who study GLP/G9a and its role in epigenetic regulation of inflammatory responses, created a strain of mice that enables conditional removal of this complex in various cell types, including neurons in the adult brain.

First author Anne Schaefer, a senior research associate in Greengard’s lab, subjected these mice to a battery of behavioral tests and determined that they behave much like humans with a mental retardation syndrome called the 9q34 deletion syndrome, in which the region of chromosome 9 that codes for the GLP genes is missing. The mice lacking GLP/G9a, unlike their normal counterparts, were not afraid of open space, were lethargic (and as a result, obese) and had problems learning to adapt to their environment.

The researchers compared the brains of normal mice and the conditional knockouts and found that there were no structural differences between them. In other words, the behavioral and learning problems associated with the conditional knockouts was not due to any kind of damage to the brain’s structure or to the individual neurons.

“This suppressive epigenetic mark completely disappears in these mice, but the neurons themselves do not die and appear normal,” says Schaefer. “The mice maintain many of their basal behavioral functions such as eating and breeding, but they display abnormal behavior in response to various environmental signals.”

Schaefer and her colleagues also found that loss of GLP/G9a resulted in increased expression of genes usually found in muscles and the heart. In addition to their analysis of genes that change in the different brain regions, they used a cellular analysis technique developed in labs headed by Rockefeller scientist Nathaniel Heintz and Paul Greengard, called TRAP, which reveals transcriptional profiles by isolating the RNA messages from structurally and functionally defined individual cell populations.

“We found that several non-neuronal genes, normally suppressed by the epigenetic mark, became upregulated in the GLP/G9a conditional knockouts,” says Schaefer.

According to Schaefer and her colleagues, it’s also possible that genetically predetermined or environmentally induced changes of the epigenetic regulators controlling the methylation mark on histone H3 may be responsible for individual differences in learning and social adaptation.

The Greengard and Tarakhovsky labs have taken these findings a step further in collaboration with Eric Nestler’s lab at the Mount Sinai School of Medicine. In research reported in the January 8 issue of the journal Science, they found that repeated cocaine administration promotes cocaine preference in mice, revealing a key role for G9a in drug addiction.

Epigenetic regulators are considered the “last frontier” by pharmaceutical companies, Tarakhovsky says, because of their position in the chain of events in cell signaling. “The major excitement of these findings is that there are very few proteins known to have such key regulatory functions and are structurally well defined. That means it should be possible to design drugs that specifically interfere with their activity.”

Joseph Bonner | Newswise Science News
Further information:
http://www.rockefeller.edu

More articles from Health and Medicine:

nachricht On track to heal leukaemia
18.01.2017 | Universitätsspital Bern

nachricht Penn vet research identifies new target for taming Ebola
12.01.2017 | University of Pennsylvania

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

How gut bacteria can make us ill

18.01.2017 | Life Sciences

On track to heal leukaemia

18.01.2017 | Health and Medicine

Water - as the underlying driver of the Earth’s carbon cycle

17.01.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>