Post Doctoral Fellowships
Deborah Bourcíhis, Ph.D.
Columbia University,
Mentor: Timothy Bestor, Ph.D.
"Involvement of DNA Methylation in the Etiology of Rett Syndrome in a Mouse Model"
2-Year Award: $100,000
Final Report (November 2004)
Rett syndrome is caused by mutations in MECP2, which is considered to be a repressor of gene expression in brain. MeCP2 has a potential function as a mediator of DNA methylation in the genome, by binding to methyl-residues added to genes and converting this signal into silencing of these tagged genes. On this assumption, Rett syndrome has been classified as a methylation-related disease. However, the lack of reactivation of methylated promoters in Rett patients and Mecp2 mutant mice renders questionable the predicted involvement of MeCP2 in methylation-dependent repression. Our goal is to determine whether MeCP2 function really relies on methylation.
The analysis of single versus double-mutants is a classical genetic way to assess a functional link between two factors. To assess the functional interaction between MeCP2 and DNA methylation, we have crossed the Mecp2 mutation onto different methylation-deficient backgrounds in mice, Dnmt1 and Dnmt3L mutant mice. We did not see a detrimental cumulative effect of the two mutations, ruling out an involvement of Mecp2 in global methylation-dependent repression pathway during embryonic development. By applying a large-scale analysis of methylation patterns in brain samples from Mecp2-mutant mice and Rett patients, we also excluded a role of MeCP2 in stabilizing DNA methylation patterns.
Deborah Bourcíhis, Ph.D.Columbia University,
Mentor: Timothy Bestor, Ph.D.
"Involvement of DNA Methylation in the Etiology of Rett Syndrome in a Mouse Model"
2-Year Award: $100,000
Final Report (November 2004)
Rett syndrome is caused by mutations in MECP2, which is considered to be a repressor of gene expression in brain. MeCP2 has a potential function as a mediator of DNA methylation in the genome, by binding to methyl-residues added to genes and converting this signal into silencing of these tagged genes. On this assumption, Rett syndrome has been classified as a methylation-related disease. However, the lack of reactivation of methylated promoters in Rett patients and Mecp2 mutant mice renders questionable the predicted involvement of MeCP2 in methylation-dependent repression. Our goal is to determine whether MeCP2 function really relies on methylation.
The analysis of single versus double-mutants is a classical genetic way to assess a functional link between two factors. To assess the functional interaction between MeCP2 and DNA methylation, we have crossed the Mecp2 mutation onto different methylation-deficient backgrounds in mice, Dnmt1 and Dnmt3L mutant mice. We did not see a detrimental cumulative effect of the two mutations, ruling out an involvement of Mecp2 in global methylation-dependent repression pathway during embryonic development. By applying a large-scale analysis of methylation patterns in brain samples from Mecp2-mutant mice and Rett patients, we also excluded a role of MeCP2 in stabilizing DNA methylation patterns.