| Co-Investigator(Kenkyū-buntansha) |
ABE Takashi Iwate Medical University, School of Medicine, Department of neurology, Associate Professor, 医学部, 助教授 (30202667)
NAGANE Yuriko Iwate Medical University, School of Medicine, Department of neurology, Assistant, 医学部, 助手 (10306003)
UTSUGISAWA Kimiaki Iwate Medical University, School of Medicine, Department of neurology, Lecturer, 医学部, 講師 (00244913)
TAKAHASHI Satoshi Iwate Medical University, School of Medicine, Department of neurology, Lecturer, 医学部, 講師 (50216719)
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| Research Abstract |
Alterations in DNA 5-methyldeoxycytidine patterns appear to control gene expression for some mammalian genes in the processes of development, carcinogenesis, and aging. Methylation at the promoter region represses the interaction between transcription factors and their specific DNA sequences. We investigated changes with age in the number of methylated cytosines in the promoter region of receptor for advanced glycation end products (RAGE), amyloid precursor protein (APP), and tau genes in the human parietal cortex, using the bisulfite method, PCR, and direct sequencing.
RAGE : In the promoter region (-328〜-36), the number of methylcytosines at CpG dinucleotides was stable throughout adult life, whereas that at sites other than CpG doublet significantly decreased in cases ≧70 years old. Of the transcription factor binding sites, the number of methylcytosines in AP2 or SP1 binding sites was significantly decreased in cases ≧70 years old. These reductions of methylcytosines may increase ex
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pression of RAGE in aged human brain.
APP : Cytosines at only 13 locations were methylated in at least one of the cases studied, in -226〜-101 region of APP gene, although which is extremely GC-rich (80%) and contains 18 CpG doublets. Methylcytosines at the 13 locations was significantly decreased in cases> 70 years old. Among the transcription factor binding sequences, the number of methylcytosines in the 9-bp-long GC-rich elements was significantly decreased in cases > 70 years old.
tau protein : While the total number of methylcytosines decreased with age in a putative promoter region (97〜436) of the tau gene, the changes in methylation status differed among transcription binding sites. Cytosines in the AP2-binding sites were never methylated in any of the cases studied. Methylcytosines in the SP1-binding sites significantly increased with age, whereas those in the binding sites for GCF, a repressor of GC-rich promoters, significantly decreased with age. These alterations in methylation status with age may decrease transcriptional activity of the tau gene in the human cerebral cortex. Less
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