Dissociation of IGF2 and H19 imprinting in human brain.
The human IGF2 and H19 genes are imprinted in most normal tissues. Alterations of genomic imprinting or loss of imprinting (LOI) have been observed in a number of malignant tumors. Although LOI has been linked to tumorigenesis, loss of IGF2 imprinting has also been observed in choroid plexus and leptomeninges in normal mouse brain. We have therefore analyzed the allelic expression of both IGF2 and H19 in human fetal brain and in different regions of human adult brain. In the brains of fetuses of 6-12 weeks gestation, both IGF2 and H19 were transcribed from both parental alleles. In contrast, strictly monoallelic expression of both IGF2 and H19 was observed in all other fetal tissues, suggesting a tissue-specific LOI in the central nervous system. In adult brain, LOI of IGF2 was region-specific. IGF2 was expressed from both parental alleles in the pons, but not in globus palludus, Raphe nucleus and hypothalamus. H19 expression was drastically reduced in adult brain compared to fetal brain, and was detectable only in the pons and globus palludus. In contrast to IGF2, the expression of H19 in adult pons was monoallelic. Examination of IGF2 promoter usage indicated predominant utilization of promoter P3 in all fetal and adult brain tissues. The LOI of IGF2 therefore reflects biallelic expression from the predominant promoter. IGF2 transcripts derived from the less abundant promoter P1, however, showed monoallelic expression in the adult pons. Our results suggest that IGF2 and H19 undergo ontogenetic changes in allelic expression and that there is dissociation of IGF2 and H19 imprinting in both fetal and adult human brain.
Pham
N V
NV
Medical Service and Geriatric Research Education and Clinical Center, VA Palo Alto Health Care System and Department of Medicine, Stanford University, Palo Alto, CA 94304, USA.
Nguyen
M T
MT
Hu
J F
JF
Vu
T H
TH
Hoffman
A R
AR
D000375:Aging / Q000378:metabolism; D000483:Alleles; D001923:Brain Chemistry / Q000235:genetics*; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D017931:DNA Primers; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis* / Q000235:genetics; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D014018:Tissue Distribution
D017931:DNA Primers; D012313:RNA; D007335:Insulin-Like Growth Factor II; D004247:DNA