Research Awards
Gert Jan C. Veenstra, Ph.D.
Nijmegen Center for Molecular Life Sciences, The Netherlands
"MeCP2-dependent epigenetic stability"
2-Year Award: $100,000
Research Sponsor: Sheila Johnson
Final Report (November 2005)
To design strategies to treat Rett Syndrome (RTT) or to alleviate its symptoms, it is essential to understand why and how mutations in MeCP2 lead to disease. Whereas it is clear that MeCP2 is able to switch off genes, it is not known how this leads to disease, as no major differences in gene regulation have been found in for example the mouse model for RTT. We are testing the possibility that, although most cells regulate genes normally in the absence of MeCP2, the cells may be less stable in the way they commit themselves to switching genes on and off. We are investigating the influence on epigenetic stability (stability in gene regulation) using embryonic cells from Xenopus laevis, which is an ideal model system for this type of research question. We have elucidated the genomic structure of MeCP2 in Xenopus and determined the precise sequence of two MeCP2 isoforms. Furthermore, we have established a robust antisense knockdown of MeCP2. We will continue to work on MeCP2 and epigenetic stability of cellular differentiation and gene regulation for at least another three years. Our ability to allocate funds to this project is a direct result of the work funded by the RSRF. We will employ the antisense knockdown of MeCP2 in a number of ways. First, we will further examine the contribution of MeCP2 to epigenetic stability of cell fates. Second, we will also use the knockdown-rescue assay to test xMeCP2 mutants in a functional assay. Third, we will examine the developmental regulation of xMeCP2 binding to methylated DNA and the potential involvement of post-translational modifications in this phenomenon.
Gert Jan C. Veenstra, Ph.D.Nijmegen Center for Molecular Life Sciences, The Netherlands
"MeCP2-dependent epigenetic stability"
2-Year Award: $100,000
Research Sponsor: Sheila Johnson
Final Report (November 2005)
To design strategies to treat Rett Syndrome (RTT) or to alleviate its symptoms, it is essential to understand why and how mutations in MeCP2 lead to disease. Whereas it is clear that MeCP2 is able to switch off genes, it is not known how this leads to disease, as no major differences in gene regulation have been found in for example the mouse model for RTT. We are testing the possibility that, although most cells regulate genes normally in the absence of MeCP2, the cells may be less stable in the way they commit themselves to switching genes on and off. We are investigating the influence on epigenetic stability (stability in gene regulation) using embryonic cells from Xenopus laevis, which is an ideal model system for this type of research question. We have elucidated the genomic structure of MeCP2 in Xenopus and determined the precise sequence of two MeCP2 isoforms. Furthermore, we have established a robust antisense knockdown of MeCP2. We will continue to work on MeCP2 and epigenetic stability of cellular differentiation and gene regulation for at least another three years. Our ability to allocate funds to this project is a direct result of the work funded by the RSRF. We will employ the antisense knockdown of MeCP2 in a number of ways. First, we will further examine the contribution of MeCP2 to epigenetic stability of cell fates. Second, we will also use the knockdown-rescue assay to test xMeCP2 mutants in a functional assay. Third, we will examine the developmental regulation of xMeCP2 binding to methylated DNA and the potential involvement of post-translational modifications in this phenomenon.