No abstract

The H19 locus belongs to a cluster of imprinted genes that is linked to the human Beckwith-Wiedemann syndrome. The expression of H19 and its closely associated IGF2 gene is frequently deregulated in some human tumors, such as Wilms' tumors. In these cases, biallelic IGF2 expression and lack of expression of H19 are associated with hypermethylation of the imprinting center of this locus. These observations and others have suggested a potential tumor suppressor effect of the H19 locus. Some studies have also suggested that H19 is an oncogene, based on tissue culture systems. We show, using in vivo murine models of tumorigenesis, that the H19 locus controls the size of experimental teratocarcinomas, the number of polyps in the Apc murine model of colorectal cancer and the timing of appearance of SV40-induced hepatocarcinomas. The H19 locus thus clearly displays a tumor suppressor effect in mice.genomic imprinting ͉ Igf2 ͉ murine models T he H19-Igf2 locus is subject to genomic imprinting and has often been used as a paradigm for the study of this particular epigenetic regulation. The H19 locus produces a 2.5-kb noncoding, spliced, and polyadenylated RNA of yet-unknown function (1, 2). The Igf2 gene encodes a fetal growth factor, insulin-like growth factor 2. These two genes are located 90 kb apart and are oppositely imprinted: H19 is maternally expressed and Igf2 paternally expressed (1, 3). They belong to a large imprinted domain localized on chromosome 7 in mice and chromosome 11p15.5 in humans. The imprinting of Igf2 and H19 is controlled by a region located 4 kb upstream from the H19 transcription unit, defined as the H19 differentially methylated region (DMR) or imprinting control region (ICR) (4).The 11p15.5-imprinted domain is linked to the BeckwithWiedemann syndrome (BWS), which is characterized by overgrowth phenotypes of affected children as well as a predisposition to develop embryonal tumors such as Wilms' tumor or rhabdomyosarcomas (5). Among the molecular alterations involved in BWS, certain cases (20%) show paternal uniparental disomy (UPD); other cases (5-10%) have hypermethylation of the H19 DMR; and both lead to lack of expression of H19 as well as activation of IGF2. These patients have higher risk of developing tumors than patients with other molecular defects (6). Genetic and epigenetic alterations at 11p15.5 similar to those found in the BWS have also been demonstrated in nonsyndromic Wilms' tumors. A great number of these cases have either loss of the maternal allele (LOH) or LOI (7,8). It has thus been suggested that the H19 gene could have a possible tumor suppressor function (9). The first direct evidence for this tumor suppressor function was provided by in vitro experiments in which transfection of H19 cDNA into G401-transformed kidney cells resulted in loss of tumorigenicity of these cells (10). Subsequent experiments performed with in vitro culture systems suggested that H19 played a role as an oncogene rather than a tumor suppressor gene (11,12). This controversy has not yet been reso...

The H19 gene encodes a 2.3-kb non-coding mRNA which is strongly expressed during embryogenesis. This gene belongs to an imprinted cluster, conserved on mouse chromosome 7 and human chromosome 11p15. H19 is maternally expressed and the neighbouring Igf2 gene is transcribed from the paternal allele. These two genes are co-expressed in endoderm- and mesoderm-derived tissues during embryonic development, which suggests a common mechanism of regulation. The regulatory elements (imprinted con- trol region, CTCF insulation, different enhancer sequences, promoters of the two genes, matrix attachment regions) confer a differential chromatin architecture to the two parental alleles leading to reciprocal expression. The role of the H19 gene is unclear but different aspects have been proposed. H19 influences growth by way of a cis control on Igf2 expression. Although H19^–/– mice are viable, a role for this gene during development has been suggested by viable H19^–/– parthenogenetic mice. Finally it has been described as a putative tumour suppressor gene. H19 has been studied by numerous laboratories over the last fifteen years, nevertheless the function of this non-coding RNA remains to be elucidated.