Nucleosome assembly on methylated CGG triplet repeats in the fragile X mental retardation gene 1 promoter.
Expansion and methylation of CGG repeat sequences is associated with Fragile X syndrome in humans. We have examined the consequences of CGG repeat expansion and methylation for nucleosome assembly and positioning on the Fragile X Mental Retardation gene 1 (FMR1) gene. Short unmethylated CGG repeats are not particularly favored in terms of affinity for the histone octamer or for positioning of the reconstituted nucleosome. However, upon methylation their affinity for the histone octamer increases and a highly positioned nucleosome assembles with the repeat sequences found adjacent to the nucleosomal dyad. Expansion of these CGG repeats abolishes the preferential nucleosome assembly due to methylation. Thus, the expansion and methylation of these triplet repeats can alter the functional organization of chromatin, which may contribute to alterations in the expression of the FMR1 gene and the disease phenotype.
Godde
J S
JS
Laboratory of Molecular Embryology, NICHHD, National Institutes of Health, Bethesda, Maryland 20892-5430, USA.
Kass
S U
SU
Hirst
M C
MC
Wolffe
A P
AP
D004247:DNA / Q000378:metabolism; D053938:DNA Fragmentation / Q000235:genetics; D019175:DNA Methylation; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000235:genetics*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009707:Nucleosomes / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins; D018911:Trinucleotide Repeats
D004247:DNA; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D009707:Nucleosomes; D016601:RNA-Binding Proteins; C497683:FMR1 protein, human