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 Antibiotic effective against drug-resistant bacteria in pediatric skin infections
17.02.2017 | University of California - San Diego

nachricht Tiny magnetic implant offers new drug delivery method
14.02.2017 | University of British Columbia

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: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Biocompatible 3-D tracking system has potential to improve robot-assisted surgery

17.02.2017 | Medical Engineering

Real-time MRI analysis powered by supercomputers

17.02.2017 | Medical Engineering

Antibiotic effective against drug-resistant bacteria in pediatric skin infections

17.02.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>