Zac1 Regulates an Imprinted Gene Network Critically Involved in the Control of Embryonic Growth

Summary 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 ∼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.