Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth.
Genomic imprinting is an epigenetic mechanism of regulation that restrains the expression of a small subset of mammalian genes to one parental allele. The reason for the targeting of these approximately 80 genes by imprinting remains uncertain. We show that inactivation of the maternally repressed Zac1 transcription factor results in intrauterine growth restriction, altered bone formation, and neonatal lethality. A meta-analysis of microarray data reveals that Zac1 is a member of a network of coregulated genes comprising other imprinted genes involved in the control of embryonic growth. Zac1 alters the expression of several of these imprinted genes, including Igf2, H19, Cdkn1c, and Dlk1, and it directly regulates the Igf2/H19 locus through binding to a shared enhancer. Accordingly, these data identify a network of imprinted genes, including Zac1, which controls embryonic growth and which may be the basis for the implementation of a common mechanism of gene regulation during mammalian evolution.
Varrault
Annie
A
Institut de Génomique Fonctionnelle, CNRS-UMR5203, INSERM-U661, Université Montpellier 1, Université Montpellier 2, Montpellier, F-34094, France.
Gueydan
Charlotte
C
Delalbre
Annie
A
Bellmann
Anja
A
Houssami
Souheir
S
Aknin
Cindy
C
Severac
Dany
D
Chotard
Laetitia
L
Kahli
Malik
M
Le Digarcher
Anne
A
Pavlidis
Paul
P
Journot
Laurent
L
D000818:Animals; D001724:Birth Weight; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism; D047108:Embryonic Development; D004742:Enhancer Elements, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D018392:Genomic Imprinting; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D010012:Osteogenesis; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D002135:Calcium-Binding Proteins; C493965:Cdkn1c protein, mouse; D018797:Cell Cycle Proteins; D050761:Cyclin-Dependent Kinase Inhibitor p57; C512925:Dlk1 protein, mouse; C513121:IGF2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C498423:Plagl1 protein, mouse; D014157:Transcription Factors; D007335:Insulin-Like Growth Factor II