A complex duplication created by gene targeting at the imprinted H19 locus results in two classes of methylation and correlated Igf2 expression phenotypes.
Imprinting of the mouse H19 and Igf2 genes is dependent on the presence of an intervening imprinting control region (ICR) situated 2 kb upstream of H19 and approximately 70 kb downstream of Igf2. Several recent studies have provided substantial evidence that the unmethylated maternal ICR acts as an insulator that prevents activation of Igf2 by a suite of enhancers downstream of the H19 gene. The methylated paternal ICR and H19 promoter have no activity, allowing sole activation of Igf2 expression. We have produced mice in which a duplication of the H19/Igf2 ICR produces, in each generation, two classes of methylation levels that correlated with two Igf2 imprinting phenotypes. One hypermethylated class also shows activation of the normally silent Igf2 gene, whereas the other hypomethylated class shows only slight activation of Igf2, in agreement with methylation's role in ICR function. This study describes a rare, possibly unique type of mutation that induces two distinct phenotypes in each generation.
Reed
M R
MR
Division of Biology, Beckman Research Institute of the City of Hope, 1450 E. Duarte Road, Duarte, California 91010-3011, USA.
Huang
C F
CF
Riggs
A D
AD
Mann
J R
JR
D000483:Alleles; D000818:Animals; D015139:Blotting, Southern; D018899:CpG Islands; D019175:DNA Methylation; D005220:Fathers; D005260:Female; D018390:Gene Targeting; D018392:Genomic Imprinting; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008297:Male; D051379:Mice; D008957:Models, Genetic; D009035:Mothers; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D062085:RNA, Long Noncoding; D012333:RNA, Messenger / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics
C094335:H19 long non-coding RNA; C420116:Ihit1 protein, mouse; D011506:Proteins; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II