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 Study suggests possible new target for treating and preventing Alzheimer's
02.12.2016 | Oregon Health & Science University

nachricht The first analysis of Ewing's sarcoma methyloma opens doors to new treatments
01.12.2016 | IDIBELL-Bellvitge Biomedical Research Institute

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: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>