Research Awards
Schahram Akbarian, M.D., Ph.D.
University of Massachusetts Medical School
"Post-Translational Modifications of Histones in Cerebral Cortex of Normal and of MeCP2-deficient Mice"
2-Year Award: $85,000
Research Sponsor: The Massachusetts Rett Syndrome Association
Final Report (November 2004)
The Rett disease gene, MECP2, encodes a protein that is thought to regulate chromatin structure and function. Chromatin is comprised of the genomic DNA and a variety of molecules that bind to it. These includes a type of proteins, called the histones, which are involved in the three-dimensional organization of DNA and chromatin structures. A number of different chemical „tags‰, or modifications, located at the tails of the histone proteins defines chromatin function. For example, if a gene is expressed at high levels in a particular cell, typically the surrounding histones are acetylated (acetylation is one of several chemical tags).
Current models on MECP2 function predict that this protein regulates histone acetylation in brain. Presently, many studies have been published describing the regulation of histone acetylation in cell culture systems. However, very little is known about the molecular mechanisms that regulate histone acetylation and other types of modifications, such as phosphorylation, in the brain of a living animal (= in vivo). With the support from RSRF, my laboratory undertook the effort to study how acute changes in dopamine receptor activity (dopamine is a messenge molecule for brain cells) affect histone acetylation and phosphorylation. We were able to show that acute blockade of dopamine (D2) receptors results in a striking short-term increase in levels of histone phospho-acetylation in certain subregions of the brain. Furthermore, we found out that in contrast to these impressive changes in drug-treated animals, levels of histone modifications in mutant mice with a genetic deletion of Mecp2 in brain after birth were surprisingly normal. This finding may suggest that, under certain conditions, loss of Mecp2 function does not result in a generalized alterations in chemical histone modifications in the brain.
Schahram Akbarian, M.D., Ph.D.University of Massachusetts Medical School
"Post-Translational Modifications of Histones in Cerebral Cortex of Normal and of MeCP2-deficient Mice"
2-Year Award: $85,000
Research Sponsor: The Massachusetts Rett Syndrome Association
Final Report (November 2004)
The Rett disease gene, MECP2, encodes a protein that is thought to regulate chromatin structure and function. Chromatin is comprised of the genomic DNA and a variety of molecules that bind to it. These includes a type of proteins, called the histones, which are involved in the three-dimensional organization of DNA and chromatin structures. A number of different chemical „tags‰, or modifications, located at the tails of the histone proteins defines chromatin function. For example, if a gene is expressed at high levels in a particular cell, typically the surrounding histones are acetylated (acetylation is one of several chemical tags).
Current models on MECP2 function predict that this protein regulates histone acetylation in brain. Presently, many studies have been published describing the regulation of histone acetylation in cell culture systems. However, very little is known about the molecular mechanisms that regulate histone acetylation and other types of modifications, such as phosphorylation, in the brain of a living animal (= in vivo). With the support from RSRF, my laboratory undertook the effort to study how acute changes in dopamine receptor activity (dopamine is a messenge molecule for brain cells) affect histone acetylation and phosphorylation. We were able to show that acute blockade of dopamine (D2) receptors results in a striking short-term increase in levels of histone phospho-acetylation in certain subregions of the brain. Furthermore, we found out that in contrast to these impressive changes in drug-treated animals, levels of histone modifications in mutant mice with a genetic deletion of Mecp2 in brain after birth were surprisingly normal. This finding may suggest that, under certain conditions, loss of Mecp2 function does not result in a generalized alterations in chemical histone modifications in the brain.