H19 (gene)

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H19, imprinted maternally expressed untranslated mRNA
Identifiers
Symbols H19 ; BWS; ASM; ASM1; D11S813E; MGC4485; PRO2605
External IDs Template:OMIM5
RNA expression pattern
More reference expression data
Orthologs
Template:GNF Ortholog box
Species Human Mouse
Entrez n/a n/a
Ensembl n/a n/a
UniProt n/a n/a
RefSeq (mRNA) n/a n/a
RefSeq (protein) n/a n/a
Location (UCSC) n/a n/a
PubMed search n/a n/a

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

H19, imprinted maternally expressed untranslated mRNA, also known as H19, is a human gene.[1]

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[2]. The H19 gene transcribed to an mRNA-like non-coding RNA by the RNA polymerase II and processed by capping, splicing and polyadenylation[3] At the RNA level, the secondary structure is evolutionary, conserved in mammalian species[4]. 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[5]. The H19 gene is paternally imprinted[6][7][8]. 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[9]. 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[10]. 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)[3]. 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[11]. H19 was initially isolated as a raf-regulating gene, involved in expression of α-fetoprotein in the mouse liver[2].

H19 RNA in human cancers

H19 was first described as a tumor suppressor gene[12], however in many types of human cancers, H19 RNA is highly expressed relative to the null expression in normal counterpart, for recent review[13]. 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[14]. A growth advantage was reported for bladder carcinoma cells overexpressing H19 in serum-poor medium[15]. H19 promoter is activated by E2F1 and repressed by pRB and E2F6[16], and by p53 [17]. The c-Myc oncogene directly induces the H19 RNA to potentiate tumoregenesis[18]. H19 is also involved in multidrug resistance phenotype[19].

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[20][21][22]. More striking is the predictive value of H19 RNA for tumor recurrence[23]. 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[24]. 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.

References

  1. ↑ "Entrez Gene: H19 H19, imprinted maternally expressed untranslated mRNA".
  2. ↑ 2.0 2.1 Pachnis V, Belayew A and Tilghman SM (1984) Locus unlinked to α-fetoprotein under the control of the murine raf and Rif genes. Proc Natl Acad Sci USA 81, 5523-5527. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=391738
  3. ↑ 3.0 3.1 Brannan CI, Dees EC, Ingram RS and Tilghman SM (1990) The product of the H19 gene may function as an RNA. Mol Cell biol 10, 28-36. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=360709.
  4. ↑ Juan V, Crain C, Wilson C (2000). Evidence for evolutionary conserved secondary structure in the h19 tumor suppressor RNA. Nucleic Acid Res 28, 1221-1227. http://nar.oxfordjournals.org/cgi/content/abstract/28/5/1221
  5. ↑ Cai X and Cullen BR (2007) The imprinted H19 noncoding RNA is a primary microRNA precursor. RNA 13, 313-316. http://www.rnajournal.org/cgi/content/full/13/3/313
  6. ↑ Bartolomei MS, Zemel S and Tilghman SM (1991) Parental imprinting of the mouse H19 gene. Nature 351, 153-155. http://www.nature.com/nature/journal/v351/n6322/abs/351153a0.html
  7. ↑ Rachmilewitz J, Goshen R, Ariel I, Schneider T, de Groot N and Hochberg A (1992) Parental imprinting of the human H19 gene. FEBS Lett 309, 25-28. http://adsabs.harvard.edu/abs/1991Natur.351..153B
  8. ↑ Zhang Y and Tycko B (1992) Monoallelic expression of the human H19 gene. Nat Genet 1, 40-44. http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&dopt=AbstractPlus&list_uids=1363808
  9. ↑ Bell AC and Felsenfeld G (2000) Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405, 482-485. http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&uid=10839546&cmd=showdetailview&indexed=google
  10. ↑ Leibovitch MP, Nguyen VC, Gross MS, Solhonne B, Leibovitch SA and Bernheim A (1991) The human ASM (adult skeletal muscle) gene: expression and chromosomal assignment to 11p15. Biochem Biophys Res Commun 180, 1241-1250. http://www.genome.jp/dbget-bin/www_bget?omim+103280
  11. ↑ Davis RL, Weintraub H and Lassar AB (1987) Expression of a single transfection cDNA converts fibroblast to myoblast. Cell 51, 987-1000.
  12. ↑ Hao Y, Crenshaw T, Moulton T, Newcomb E and Tycko B (1993) Tumor-suppressor activity of H19 RNA. Nature 365, 764-767.
  13. ↑ Matouk I, Ohana P, Ayesh S, Sidi A, Czerniak A, de-Groot N and Hochberg A (2005) The oncofetal H19 RNA in human cancer, from the bench to the patient. Cancer Therapy 3, 249-266.
  14. ↑ Matouk IJ, de-Groot N, Mezan S, Ayesh S, Abu-lail R, Hochberg A and Galun E (2007) The H19 non-coding RNA is essential for human tumor growth. PLoS ONE 2 (9), e845.
  15. ↑ Ayesh S, Matouk I, Schneider T, Ohana P, Laster M, Al-Sharef W, de-Groot N and Hochberg A (2002) Possible physiological role of H19 RNA. Mol Carcinog 35, 63-74.
  16. ↑ Berteaux N, Lottin S, Monte D, Pinte S, Quatannens B, Coll J, et al.(2005) H19 mRNA-like noncoding RNA promotes breast cancer cell proliferation through positive control by E2F1. J Biol Chem 280, 29625-26636.
  17. ↑ Dugimont T, Montpellier C, Adriaenssens E, Lottin S, Dumont L, Lotsova V, Lagrou C, Stehelin D, Coll J and Curgy JJ (1998) The H19 TATA-less promoter is efficiently repressed by the wild-type tumor suppressor gene product p53. Oncogene 16, 2395-2401.
  18. ↑ Barsyte-Lovejoy D, Lau SK, Boutros PC, Khosravi F, Jurisica I, Andrulis IL, et al. (2006) The c-Myc oncogene directly induces the H19 noncoding RNA by allele-specific binding to potentiate tumorigenesis. Cancer Res 66, 5330-5337.
  19. ↑ Tsang WP and Kwok TT (2007) Riboregulator H19 induction of MDR1-associated drug resistance in human hepatocellular carcinoma cells. Oncogene 26, 4877-4881.
  20. ↑ Ariel I, Ayesh S, Perlman EJ, Pizov G, Tanos V, Schneider T, Erdmann VA, Podeh D, Komitowski D, Quasem AS, de Groot N and Hochberg A (1997) The product of the imprinted H19 gene is an oncofetal RNA. Mol Pathol 50, 34-44.
  21. ↑ Ariel I, Lustig O, Schneider T, Pizov G, Sappir M, de Groot N and Hochberg A (1995) The imprinted H19 gene as a tumor marker in bladder carcinoma. Urology 45, 335-338.
  22. ↑ Ariel I, Miao H.Q, Ji XR, Schneider T, Roll D, de Groot N, Hochberg A and Ayesh S (1998) Imprinted H19 oncofetal RNA is a candidate tumor marker for hepatocellular carcinoma. Mol Pathol 51, 21-25.
  23. ↑ Ariel I, Sughayer M, Fellig Y, Pizo G, Ayesh S, Podeh D, Libdeh BA, Levy C, Birman T, Tykocinski ML, de Groot N and Hochberg A (2000) The imprinted H19 gene is a marker of early recurrence in human bladder carcinoma. Mol Pathol 53, 320-323.
  24. ↑ Ohana P, Gofrit O, Ayesh S, Al-Sharef W, Mizrahi A, Birman T, Schneider T, Matouk I, de Groot N, Tavdy E, Sidi A and Hochberg A (2004) Regulatory sequences of H19 gene in DNA based therapy of bladder cancer. Gene Ther Mol Biol. 8, 181-192.


Further reading

  • Brannan CI, Dees EC, Ingram RS, Tilghman SM (1990). "The product of the H19 gene may function as an RNA". Mol. Cell. Biol. 10 (1): 28–36. PMID 1688465.
  • Leibovitch MP, Nguyen VC, Gross MS; et al. (1991). "The human ASM (adult skeletal muscle) gene: expression and chromosomal assignment to 11p15". Biochem. Biophys. Res. Commun. 180 (3): 1241–50. PMID 1953776.
  • Glaser T, Housman D, Lewis WH; et al. (1990). "A fine-structure deletion map of human chromosome 11p: analysis of J1 series hybrids". Somat. Cell Mol. Genet. 15 (6): 477–501. PMID 2595451.
  • Ishihara K, Kato R, Furuumi H; et al. (1999). "Sequence of a 42-kb mouse region containing the imprinted H19 locus: identification of a novel muscle-specific transcription unit showing biallelic expression". Mamm. Genome. 9 (9): 775–7. PMID 9716667.
  • Ishihara K, Hatano N, Furuumi H; et al. (2000). "Comparative genomic sequencing identifies novel tissue-specific enhancers and sequence elements for methylation-sensitive factors implicated in Igf2/H19 imprinting". Genome Res. 10 (5): 664–71. PMID 10810089.
  • Dos Reis S, Coulary-Salin B, Forge V; et al. (2002). "The HET-s prion protein of the filamentous fungus Podospora anserina aggregates in vitro into amyloid-like fibrils". J. Biol. Chem. 277 (8): 5703–6. doi:10.1074/jbc.M110183200. PMID 11733532.
  • DeBaun MR, Niemitz EL, McNeil DE; et al. (2002). "Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects". Am. J. Hum. Genet. 70 (3): 604–11. PMID 11813134.
  • Gao ZH, Suppola S, Liu J; et al. (2002). "Association of H19 promoter methylation with the expression of H19 and IGF-II genes in adrenocortical tumors". J. Clin. Endocrinol. Metab. 87 (3): 1170–6. PMID 11889182.
  • Kanduri M, Kanduri C, Mariano P; et al. (2002). "Multiple nucleosome positioning sites regulate the CTCF-mediated insulator function of the H19 imprinting control region". Mol. Cell. Biol. 22 (10): 3339–44. PMID 11971967.
  • Lottin S, Adriaenssens E, Dupressoir T; et al. (2002). "Overexpression of an ectopic H19 gene enhances the tumorigenic properties of breast cancer cells". Carcinogenesis. 23 (11): 1885–95. PMID 12419837.
  • DeBaun MR, Niemitz EL, Feinberg AP (2003). "Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19". Am. J. Hum. Genet. 72 (1): 156–60. PMID 12439823.
  • Strausberg RL, Feingold EA, Grouse LH; et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMID 12477932.
  • Ng A, Tang JP, Goh CH, Hui KM (2003). "Regulation of the H19 imprinting gene expression in human nasopharyngeal carcinoma by methylation". Int. J. Cancer. 104 (2): 179–87. doi:10.1002/ijc.10926. PMID 12569573.
  • Coutinho-Camillo CM, Brentani MM, Butugan O; et al. (2003). "Relaxation of imprinting of IGFII gene in juvenile nasopharyngeal angiofibromas". Diagn. Mol. Pathol. 12 (1): 57–62. PMID 12605037.
  • Bock O, Schlué J, Kreipe H (2003). "Reduced expression of H19 in bone marrow cells from chronic myeloproliferative disorders". Leukemia. 17 (4): 815–6. doi:10.1038/sj.leu.2402830. PMID 12682647.
  • Stuhlmüller B, Kunisch E, Franz J; et al. (2003). "Detection of oncofetal h19 RNA in rheumatoid arthritis synovial tissue". Am. J. Pathol. 163 (3): 901–11. PMID 12937131.
  • Ota T, Suzuki Y, Nishikawa T; et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
  • Marques CJ, Carvalho F, Sousa M, Barros A (2004). "Genomic imprinting in disruptive spermatogenesis". Lancet. 363 (9422): 1700–2. doi:10.1016/S0140-6736(04)16256-9. PMID 15158633.
  • Sparago A, Cerrato F, Vernucci M; et al. (2004). "Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome". Nat. Genet. 36 (9): 958–60. doi:10.1038/ng1410. PMID 15314640.
  • Tessema M, Länger F, Bock O; et al. (2005). "Down-regulation of the IGF-2/H19 locus during normal and malignant hematopoiesis is independent of the imprinting pattern". Int. J. Oncol. 26 (2): 499–507. PMID 15645136.

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