Post Doctoral Fellowships
Brian Chadwick, Ph.D.
Case Western Reserve University
"Heterochromatin Protein Localization and Effect on Gene Silencing in Rett Syndrome"
Mentor: Huntington Willard, Ph.D.
2-Year Award: $100,000
Research Sponsor: Reading Rock, Inc.
Lay Final Report (September 2002):
During development, cells differentiate into a wide range of highly specialized cell types such as neurons in the brain. Coupled with these changes are specific alterations in the regimen of genes expressed. Maintaining such changes is critical for the cells maturation and function. The past decade has seen massive advances in our understanding of the regulation of gene expression. Of particular interest is the research into the family of methyl-DNA binding proteins that are implicated in repressing gene expression. Defects in one member of this group MECP2, is the molecular basis of Rett syndrome. It is thought that MECP2 mutations in Rett syndrome patients compromises the ability of MECP2 to function and consequently results in inappropriate gene expression. To investigate the effects of MECP2 mutation in Rett syndrome, we chose a cell culture based approach. We anticipated that mutations in MECP2 would not only affect its nuclear distribution, but would also affect a variety of other proteins involved in the silencing process. In order to proceed with our investigation, several technical considerations were accomplished, including immortalizing and separating mutant cells from normal cells. We determined conditions to investigate a large number of components involved in gene regulation, and made comparisons between the mutant and normal cell lines. Surprisingly, other than MECP2 itself, no distribution changes were found with any of the proteins investigated including factors known to interact with MECP2. From this we conclude that while in most cases MECP2's role is redundant, likely only a handful of sites in the nucleus are absolutely dependent upon the function of MECP2. Homing in on these regions and monitoring the changes bought about by mutant MECP2 will allow more focused investigation into the devastating pathology in Rett syndrome.
Brian Chadwick, Ph.D.Case Western Reserve University
"Heterochromatin Protein Localization and Effect on Gene Silencing in Rett Syndrome"
Mentor: Huntington Willard, Ph.D.
2-Year Award: $100,000
Research Sponsor: Reading Rock, Inc.
Lay Final Report (September 2002):
During development, cells differentiate into a wide range of highly specialized cell types such as neurons in the brain. Coupled with these changes are specific alterations in the regimen of genes expressed. Maintaining such changes is critical for the cells maturation and function. The past decade has seen massive advances in our understanding of the regulation of gene expression. Of particular interest is the research into the family of methyl-DNA binding proteins that are implicated in repressing gene expression. Defects in one member of this group MECP2, is the molecular basis of Rett syndrome. It is thought that MECP2 mutations in Rett syndrome patients compromises the ability of MECP2 to function and consequently results in inappropriate gene expression. To investigate the effects of MECP2 mutation in Rett syndrome, we chose a cell culture based approach. We anticipated that mutations in MECP2 would not only affect its nuclear distribution, but would also affect a variety of other proteins involved in the silencing process. In order to proceed with our investigation, several technical considerations were accomplished, including immortalizing and separating mutant cells from normal cells. We determined conditions to investigate a large number of components involved in gene regulation, and made comparisons between the mutant and normal cell lines. Surprisingly, other than MECP2 itself, no distribution changes were found with any of the proteins investigated including factors known to interact with MECP2. From this we conclude that while in most cases MECP2's role is redundant, likely only a handful of sites in the nucleus are absolutely dependent upon the function of MECP2. Homing in on these regions and monitoring the changes bought about by mutant MECP2 will allow more focused investigation into the devastating pathology in Rett syndrome.