International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


Marika Charalambous
Developmental Biology Program
School of Biology and Biochemistry
University of Bath
Claverton Down
Bath BA2 7AY

Co-Author:  Ward A
Institution:   Developmental Biology Program, University of Bath

An enhancer element at the igf2/h19 locus drives gene expression in both imprinted and non-imprinted tissues

The Insulin-like growth factor 2 (Igf2) and H19 genes lie within 100kb of each other on mouse chromosome 7, and are thought to share cis- elements necessary for both expression and imprinting. The paternally expressed Igf2 gene encodes a fetal growth factor, and the maternally expressed H19 gene a non-coding RNA of unknown function. In the developing endodermal tissues, imprinting of these genes is thought to be mediated by the interaction of a set of enhancers downstream of the H19 gene with a differentially methylated domain (DMD) that lies approximately 2-4kb upstream of H19. In the remainder of tissues that express Igf2 and H19, the cis- elements that drive their correct expression and imprinting are not well understood, but may rely upon the differential methylation of several sites proximal to the Igf2 gene. In addition, the enhancers driving the expression of Igf2 in the choroid plexus and leptomeninges, tissues where the gene is not imprinted, have not been isolated.

Approximately 32kb upstream of the mouse H19 gene lies a region containing two blocks of strong sequence conservation between mouse and human, and that exhibits DNaseI hypersensitivity and hypomethylation relative to the surrounding. We have created transgenes containing 2kb of genomic DNA containing this region, that we have termed the centrally conserved domain (CCD), in-cis to a Igf2-promoter 3-LacZ reporter gene. Transgenic mice bearing these constructs show reporter gene expression in a variety of tissues where Igf2 is normally expressed, including the choroid plexus, leptomeninges, tongue, facial mesenchyme and lens of the eye. We propose that this intergenic region functions as an enhancer for Igf2 both in tissues where the gene is imprinted, and in regions where Igf2 is biallelically expressed. The existence of an enhancer for imprinted tissues in the intergenic region argues for the existence of imprinting controls distinct from the DMD, which may be provided by differential methylation proximal to Igf2.

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