TY - JOUR
T1 - Molecular mechanisms of age-related regulation of genes
AU - Kurachi, Kotoku
AU - Kurachi, Sumiko
AU - Zhang, Kezhong
AU - Ameri, Afshin
AU - Huo, Jeffrey
AU - Kuwahara, Mitsuhiro
AU - Fontaine, Jean Marc
AU - Abe, Takahiro
PY - 2004/5/1
Y1 - 2004/5/1
N2 - Through transgenic mouse analyses of age-related expression of human genes, we recently discovered the first molecular mechanism of age-related regulation of gene expression, a critical finding for understanding the age-dimension homeostasis. In our study, human genes for blood coagulation factor IX (FIX) and anti-coagulant protein C (PC), which show age-dependent increasing and stable expression patterns, respectively, were subjected to systematic in vitro and in vivo analyses. The mechanism found uses two genetic elements, age-related stability elements (ASEs, G/CAGGAAG) and age-related increase element (AIE, a stretch of dinucleotide repeats). ASE is required for age-related stable patterns of gene expression as seen for the human PC (hPC) gene, whereas a combination of ASE and AIE is required for age-related increase patterns of gene expression as seen for the human FIX gene. ASE functions not only for temporal regulation but also for precise spatial regulation of gene expression. Differential and combined usages of ASE and AIE apparently generate specific age-related regulatory patterns of different genes. Transgenic mice persistently over-expressing hFIX at high levels died at much younger ages than expected. These animals developed not only thromboses in tissues such as heart, brain and lung but also generated myocardial fibrosis in the left ventricle, mimicking a type of human myocardial infarction. These findings laid the foundation for developing a new research field, age-dimension technology (ADT), which explores useful applications of the mechanisms of age-dimension homeostasis.
AB - Through transgenic mouse analyses of age-related expression of human genes, we recently discovered the first molecular mechanism of age-related regulation of gene expression, a critical finding for understanding the age-dimension homeostasis. In our study, human genes for blood coagulation factor IX (FIX) and anti-coagulant protein C (PC), which show age-dependent increasing and stable expression patterns, respectively, were subjected to systematic in vitro and in vivo analyses. The mechanism found uses two genetic elements, age-related stability elements (ASEs, G/CAGGAAG) and age-related increase element (AIE, a stretch of dinucleotide repeats). ASE is required for age-related stable patterns of gene expression as seen for the human PC (hPC) gene, whereas a combination of ASE and AIE is required for age-related increase patterns of gene expression as seen for the human FIX gene. ASE functions not only for temporal regulation but also for precise spatial regulation of gene expression. Differential and combined usages of ASE and AIE apparently generate specific age-related regulatory patterns of different genes. Transgenic mice persistently over-expressing hFIX at high levels died at much younger ages than expected. These animals developed not only thromboses in tissues such as heart, brain and lung but also generated myocardial fibrosis in the left ventricle, mimicking a type of human myocardial infarction. These findings laid the foundation for developing a new research field, age-dimension technology (ADT), which explores useful applications of the mechanisms of age-dimension homeostasis.
KW - Age-dimension technology
KW - Age-related regulation of genes
KW - Molecular
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U2 - 10.1016/j.ics.2004.02.166
DO - 10.1016/j.ics.2004.02.166
M3 - Article
AN - SCOPUS:85023024421
SN - 0531-5131
VL - 1262
SP - 562
EP - 565
JO - International Congress Series
JF - International Congress Series
IS - C
ER -