H19 acts as a trans regulator of the imprinted gene network controlling growth in mice.
The imprinted H19 gene produces a non-coding RNA of unknown function. Mice lacking H19 show an overgrowth phenotype, due to a cis effect of the H19 locus on the adjacent Igf2 gene. To explore the function of the RNA itself, we produced transgenic mice overexpressing H19. We observed postnatal growth reduction in two independent transgenic lines and detected a decrease of Igf2 expression in embryos. An extensive analysis of several other genes from the newly described imprinted gene network (IGN) was performed in both loss- and gain-of-function animals. We found that H19 deletion leads to the upregulation of several genes of the IGN. This overexpression is restored to the wild-type level by transgenic expression of H19. We therefore propose that the H19 gene participates as a trans regulator in the fine-tuning of this IGN in the mouse embryo. This is the first in vivo evidence of a functional role for the H19 RNA. Our results also bring further experimental evidence for the existence of the IGN and open new perspectives in the comprehension of the role of genomic imprinting in embryonic growth and in human imprinting pathologies.
Gabory
Anne
A
Genetics and Development Department, Inserm U567, CNRS UMR 8104, University of Paris Descartes, Institut Cochin, Paris, France.
Ripoche
Marie-Anne
MA
Le Digarcher
Anne
A
Watrin
Françoise
F
Ziyyat
Ahmed
A
Forné
Thierry
T
Jammes
Hélène
H
Ainscough
Justin F X
JF
Surani
M Azim
MA
Journot
Laurent
L
Dandolo
Luisa
L
D000818:Animals; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid
C094335:H19 long non-coding RNA; C513121:IGF2 protein, mouse; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II