Genomic deletion of an imprint maintenance element abolishes imprinting of both insulin-like growth factor II and H19.
Insulin-like growth factor II (Igf2) is maternally imprinted in normal tissues with only the paternal copy of the gene being transcribed, whereas the contiguous gene H19 is paternally imprinted. Dysregulation of IGF2 imprinting is commonly observed in Wilms' tumor and other human tumors. Previous work comparing promoter-specific imprinting of human and mouse Igf2 suggested the presence of a cis element upstream of Igf2 that regulates or maintains the imprinting of three downstream promoters. To explore the molecular mechanism of maintenance of genomic imprinting, we targeted the region between insulin 2 and Igf2, where the cis imprint maintenance element (IME) resides in mouse fibroblasts. In those clones in which the targeting vector was randomly integrated into the genome, mouse Igf2 remained imprinted. However, when the targeted region containing the IME was deleted by homologous recombination, whether from the paternal or maternal allele, activation of the imprinted maternal allele of Igf2 was observed. In addition, there was a loss of H19 imprinting when the IME was deleted. The requirement of IME from both parental alleles for the maintenance of genomic imprinting thus suggests the importance of a spatial structure of DNA around Igf2 and H19. Modifications in the IME, like abnormal methylation in Wilms' tumors, may represent a novel mechanism for loss of genomic imprinting.
Hu
J F
JF
Medical Service and GRECC, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, USA.
Vu
T H
TH
Hoffman
A R
AR
D000818:Animals; D017353:Gene Deletion; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated
C094335:H19 long non-coding RNA; D009124:Muscle Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II