H19 (gene)

For other uses of "H19" see the H19 (disambiguation).

H19, imprinted maternally expressed untranslated mRNA, also known as H19, is a human gene.

The H19 gene was discovered in 1984 as one of the genes that show coordinate regulation with the alpha-fetoprotein gene in the mouse liver. The H19 gene transcribed to an mRNA-like non-coding RNA by the RNA polymerase II and processed by capping, splicing and polyadenylation At the RNA level, the secondary structure is evolutionary, conserved in mammalian species. However, the absence of conservation at the potential protein levels indicates that the mature transcript is the functional product of the H19 gene. Recently, a microRNA miR-675 was described and produced from exon-1 of the H19 gene. The H19 gene is paternally imprinted. The imprinted status is mediated by a differentially methylated domain, which forms an active CTCF-dependent insulator on the maternal allele, and governs the expression of H19 and repression of IGF2 genes. In the male germline, the DMD acquire methylation that is necessary for repression of the paternal H19 allele.

Mapping isolation and gene structure
H19 mapped on the short arm of chromosome 11, band 15.5, homologous to a region of murine chromosome 7. Both physical and functional locations of H19 gene within the cluster of the imprinted genes are conserved between human and mice. The genes isolated from humans and mice consist of five exons separated by unusually short introns (80-96 nucleotides in humans). The H19 gene was isolated by differential cDNA cloning from murine embryonic stem cells, which differentiate in vitro to embryoid bodies and as one of the genes (referred to as MyoH) involved in differentiation of myoblasts. H19 was initially isolated as a raf-regulating gene, involved in expression of α-fetoprotein in the mouse liver.

H19 RNA in human cancers
H19 was first described as a tumor suppressor gene, however in many types of human cancers, H19 RNA is highly expressed relative to the null expression in normal counterpart, for recent review. This may be associated with loss of imprinting in many cases. "Loss of imprinting" is a term that is conventionally used to describe the change from imprinted monoallelic expression and in most cases with an increase of expression. Recently, the oncogenic properties of the H19 RNA have been established. It was shown that H19 RNA is essential for human tumor growth, and is a hypoxia-responsive gene. A growth advantage was reported for bladder carcinoma cells overexpressing H19 in serum-poor medium. H19 promoter is activated by E2F1 and repressed by pRB and E2F6, and by p53. The c-Myc oncogene directly induces the H19 RNA to potentiate tumoregenesis. H19 is also involved in multidrug resistance phenotype.

Clinical significance
The increased expression of H19 in many tumors relevant to its null expression in corresponding normal tissues enforces its utility as a tumor marker. More striking is the predictive value of H19 RNA for tumor recurrence. Treatment of bladder carcinoma in animals and human patients, with constructs expressing the Diphtheria Toxin A (DT-A) gene driven by H19 regulatory sequences, lead to a highly significant suppression of tumor growth in animals and human patients. Moreover, there is no apparent toxicity to the host, indicating that these constructs have a high therapeutic potential and are very promising candidates for bladder cancer therapy in humans. Significant tumor reduction has also been demonstrated in a patient with colon metastases in the liver following intra-tumoral injection of the DTA-H19 plasmid, while another patient suffering from large colon metastases in the liver showed no side effects following intra-arterial administration of toxin plasmid, which remained in the blood and urine for a number of hours. A Phase I/IIa clinical study was carried out under FDA guidelines at two medical centers in Israel. This study was designed to assess the safety and preliminary efficacy of five different doses of DTA-H19, given as six intravesical infusions into the bladder of patients with superficial bladder cancer who had failed intravesical therapy with BCG, the current standard of treatment. No Serious Adverse Events (SAE) related to the plasmid treatment (up to a dose of 20 mg) and no disease progression were detected throughout the trial.