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Gene Review

H19  -  H19, imprinted maternally expressed...

Mus musculus

Synonyms: AI747191
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Disease relevance of H19


High impact information on H19

  • Various chromatin models have been proposed that separate Igf2 and H19 into active and silent domains [6].
  • Here we used a GAL4 knock-in approach as well as the chromosome conformation capture technique to show that the differentially methylated regions in the imprinted genes Igf2 and H19 interact in mice [6].
  • Differentially methylated regions in Igf2 and H19 contain chromatin boundaries, silencers and activators and regulate the reciprocal expression of the two genes in a methylation-sensitive manner by allowing them exclusive access to a shared set of enhancers [6].
  • Thus, the nine CpG mutations in the DMD showed that the two parental-specific roles of the H19 DMD, methylation maintenance and insulator assembly, are antagonistic [7].
  • Deletion of a silencer element in Igf2 results in loss of imprinting independent of H19 [8].

Chemical compound and disease context of H19


Biological context of H19

  • Two of them, insulin-like growth factor-2 (Igf-2) and H19, map to the distal end of mouse chromosome 7, but are imprinted in opposite directions [11].
  • To test this hypothesis, a targeted deletion of two endoderm-specific enhancers that lie 3' of H19 was generated by homologous recombination in embryonic stem cells [12].
  • Inheritance of the enhancer deletion through the maternal lineage led to a loss of H19 gene expression in cells of endodermal origin, including cells in the liver, gut, kidney, and lung [12].
  • The expression of each gene was biallelic in the female and male germ line from the time that migratory mitotic PGCs entered the embryonic genital ridge and throughout gametogenesis, except that H19 RNA was not detected late in gametogenesis [13].
  • The identical expression during development of the 3'-most genes in the cluster, Igf2 and H19, led to the proposal that their imprinting was mechanistically linked through a common set of transcriptional regulatory elements [12].

Anatomical context of H19

  • The closely linked H19 and Igf2 genes were activated after the blastocyst stage and often exhibited biallelic and monoallelic expression respectively in tissues of pregastrulation postimplantation-stage embryos, rather than reciprocal monoallelic modes as observed at later stages [14].
  • These results establish that H19 and Igf2 utilize the same endoderm enhancers, but on different parental chromosomes [12].
  • In many of the ES fetuses, the levels of H19 expression were strongly reduced, and this biallelic repression was associated with biallellic methylation of the H19 upstream region [15].
  • We here demonstrate retention of normal differential methylation at H19, Igf2, or Kvlqt1 DMR by all of the cell lines [16].
  • We did find, however, that the H19 gene was highly expressed not only in the parthenogenetic conceptus, but also in giant trophoblasts and secondary giant cells in the androgenetic placenta, in spite of the imprinting of the H19 gene in normal mouse extra embryonic tissues [17].

Associations of H19 with chemical compounds

  • Physical linkage of two mammalian imprinted genes, H19 and insulin-like growth factor 2 [11].
  • Levels of H19 transcripts in aorta correlated positively with plasma total homocysteine concentration (p < 0.05, r = 0.620) [1].
  • By using Southern blots and the bisulfite genomic-sequencing technique, we have investigated the allelic methylation patterns (epigenotypes) of the Igf2 gene in two strains of mouse with distinct deletions of the H19 gene [18].
  • Igf2, H19 and Igf2r were all appropriately expressed in the PGES derived cells following induction of differentiation in vitro with all-trans retinoic acid or DMSO, when compared with control (D3) and androgenetic ES cells (AGES) [19].
  • Previous observations from a limited analysis have suggested that methylation of a few CpG dinucleotides in the region upstream from the start of transcription may be the mark that confers parental identity to the H19 alleles [20].

Physical interactions of H19

  • Here we document that point mutations of the nucleotides in physical contact with CTCF within the endogenous H19 ICR lead to loss of CTCF binding and Igf2 imprinting only when passaged through the female germline [21].
  • H19 RNA binds four molecules of insulin-like growth factor II mRNA-binding protein [22].

Enzymatic interactions of H19

  • The interactions between the enhancers and the genes are regulated by the DMR, which works as a selector by exerting dual functions: a methylated DMR on the paternal chromosome inactivates adjacent H19 and an unmethylated DMR on the maternal chromosome insulates Igf2 from the enhancers [23].

Regulatory relationships of H19

  • Loss of the maternal H19 gene induces changes in Igf2 methylation in both cis and trans [18].
  • Indeed, our results indicate that overexpression of c-mos protein in the muscle cell line C2C12 induces a concomitant increase of H19 mRNA expression [24].

Other interactions of H19

  • Igf-2 lies approximately 90 kilobases of DNA 5' to H19, in the same transcriptional orientation [11].
  • The mRNA levels of H19, Igf2r and Igf-2 and the degree of methylation at specific associated sequences were correlated according to previous studies in embryos, and thereby are consistent with suggestions that the methylation might play a role in controlling transcription of these genes [25].
  • Three of the four known imprinted genes (Igf-2, H19, and Snrpn) map to mouse chromosome 7 [26].
  • A DNA mapping panel derived from an interspecific backcross was used to position the mouse insulin-2 locus (Ins-2) on Chromosome 7, near H19 (0/114 recombinants) and Th (1/114 recombinants) [27].
  • The imprinting of the Igf2 and Ins2 genes is dependent on the transcription of the downstream H19 gene [28].

Analytical, diagnostic and therapeutic context of H19


  1. Tissue-specific changes in H19 methylation and expression in mice with hyperhomocysteinemia. Devlin, A.M., Bottiglieri, T., Domann, F.E., Lentz, S.R. J. Biol. Chem. (2005) [Pubmed]
  2. Comparative analysis of Igf-2/H19 imprinted domain: identification of a highly conserved intergenic DNase I hypersensitive region. Koide, T., Ainscough, J., Wijgerde, M., Surani, M.A. Genomics (1994) [Pubmed]
  3. Expression of insulin-like growth factor II (IGF)-II) and H19 in murine teratocarcinomas derived from embryonic stem (ES) cells. Blythe, N.L., Senior, P.V., Beck, F. J. Anat. (1996) [Pubmed]
  4. Metastasizing mammary carcinomas in H19 enhancers-Igf2 transgenic mice. Pravtcheva, D.D., Wise, T.L. J. Exp. Zool. (1998) [Pubmed]
  5. Expression of H19 and Igf2 genes in uniparental mouse ES cells during in vitro and in vivo differentiation. McKarney, L.A., Overall, M.L., Dziadek, M. Differentiation (1996) [Pubmed]
  6. Interaction between differentially methylated regions partitions the imprinted genes Igf2 and H19 into parent-specific chromatin loops. Murrell, A., Heeson, S., Reik, W. Nat. Genet. (2004) [Pubmed]
  7. Antagonism between DNA hypermethylation and enhancer-blocking activity at the H19 DMD is uncovered by CpG mutations. Engel, N., West, A.G., Felsenfeld, G., Bartolomei, M.S. Nat. Genet. (2004) [Pubmed]
  8. Deletion of a silencer element in Igf2 results in loss of imprinting independent of H19. Constância, M., Dean, W., Lopes, S., Moore, T., Kelsey, G., Reik, W. Nat. Genet. (2000) [Pubmed]
  9. Steroid hormones modulate H19 gene expression in both mammary gland and uterus. Adriaenssens, E., Lottin, S., Dugimont, T., Fauquette, W., Coll, J., Dupouy, J.P., Boilly, B., Curgy, J.J. Oncogene (1999) [Pubmed]
  10. Association of H19 promoter methylation with the expression of H19 and IGF-II genes in adrenocortical tumors. Gao, Z.H., Suppola, S., Liu, J., Heikkilä, P., Jänne, J., Voutilainen, R. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  11. Physical linkage of two mammalian imprinted genes, H19 and insulin-like growth factor 2. Zemel, S., Bartolomei, M.S., Tilghman, S.M. Nat. Genet. (1992) [Pubmed]
  12. An enhancer deletion affects both H19 and Igf2 expression. Leighton, P.A., Saam, J.R., Ingram, R.S., Stewart, C.L., Tilghman, S.M. Genes Dev. (1995) [Pubmed]
  13. Biallelic expression of imprinted genes in the mouse germ line: implications for erasure, establishment, and mechanisms of genomic imprinting. Szabó, P.E., Mann, J.R. Genes Dev. (1995) [Pubmed]
  14. Allele-specific expression and total expression levels of imprinted genes during early mouse development: implications for imprinting mechanisms. Szabó, P.E., Mann, J.R. Genes Dev. (1995) [Pubmed]
  15. Altered imprinted gene methylation and expression in completely ES cell-derived mouse fetuses: association with aberrant phenotypes. Dean, W., Bowden, L., Aitchison, A., Klose, J., Moore, T., Meneses, J.J., Reik, W., Feil, R. Development (1998) [Pubmed]
  16. Loss of Igf2 imprinting in monoclonal mouse hepatic tumor cells is not associated with abnormal methylation patterns for the H19, Igf2, and Kvlqt1 differentially methylated regions. Ishizaki, T., Yoshie, M., Yaginuma, Y., Tanaka, T., Ogawa, K. J. Biol. Chem. (2003) [Pubmed]
  17. The non-viability of uniparental mouse conceptuses correlates with the loss of the products of imprinted genes. Walsh, C., Glaser, A., Fundele, R., Ferguson-Smith, A., Barton, S., Surani, M.A., Ohlsson, R. Mech. Dev. (1994) [Pubmed]
  18. Loss of the maternal H19 gene induces changes in Igf2 methylation in both cis and trans. Forné, T., Oswald, J., Dean, W., Saam, J.R., Bailleul, B., Dandolo, L., Tilghman, S.M., Walter, J., Reik, W. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  19. A functional analysis of imprinting in parthenogenetic embryonic stem cells. Allen, N.D., Barton, S.C., Hilton, K., Norris, M.L., Surani, M.A. Development (1994) [Pubmed]
  20. A 5' 2-kilobase-pair region of the imprinted mouse H19 gene exhibits exclusive paternal methylation throughout development. Tremblay, K.D., Duran, K.L., Bartolomei, M.S. Mol. Cell. Biol. (1997) [Pubmed]
  21. The nucleotides responsible for the direct physical contact between the chromatin insulator protein CTCF and the H19 imprinting control region manifest parent of origin-specific long-distance insulation and methylation-free domains. Pant, V., Mariano, P., Kanduri, C., Mattsson, A., Lobanenkov, V., Heuchel, R., Ohlsson, R. Genes Dev. (2003) [Pubmed]
  22. H19 RNA binds four molecules of insulin-like growth factor II mRNA-binding protein. Runge, S., Nielsen, F.C., Nielsen, J., Lykke-Andersen, J., Wewer, U.M., Christiansen, J. J. Biol. Chem. (2000) [Pubmed]
  23. Mechanisms of Igf2/H19 imprinting: DNA methylation, chromatin and long-distance gene regulation. Sasaki, H., Ishihara, K., Kato, R. J. Biochem. (2000) [Pubmed]
  24. Direct relationship between the expression of tumor suppressor H19 mRNA and c-mos proto-oncogene during myogenesis. Leibovitch, M.P., Solhonne, B., Guillier, M., Verrelle, P., Leibovitch, S.A., Verelle P [corrected to Verrelle, P. Oncogene (1995) [Pubmed]
  25. Expression and methylation of imprinted genes during in vitro differentiation of mouse parthenogenetic and androgenetic embryonic stem cell lines. Szabó, P., Mann, J.R. Development (1994) [Pubmed]
  26. Spatially restricted imprinting of mouse chromosome 7. Villar, A.J., Pedersen, R.A. Mol. Reprod. Dev. (1994) [Pubmed]
  27. Localization of insulin-2 (Ins-2) and the obesity mutant tubby (tub) to distinct regions of mouse chromosome 7. Jones, J.M., Meisler, M.H., Seldin, M.F., Lee, B.K., Eicher, E.M. Genomics (1992) [Pubmed]
  28. Matrix-attachment regions in the mouse chromosome 7F imprinted domain. Greally, J.M., Guinness, M.E., McGrath, J., Zemel, S. Mamm. Genome (1997) [Pubmed]
  29. The structure and expression of a novel gene activated in early mouse embryogenesis. Pachnis, V., Brannan, C.I., Tilghman, S.M. EMBO J. (1988) [Pubmed]
  30. Locus unlinked to alpha-fetoprotein under the control of the murine raf and Rif genes. Pachnis, V., Belayew, A., Tilghman, S.M. Proc. Natl. Acad. Sci. U.S.A. (1984) [Pubmed]
  31. Monoallelic expression and methylation of imprinted genes in human and mouse embryonic germ cell lineages. Onyango, P., Jiang, S., Uejima, H., Shamblott, M.J., Gearhart, J.D., Cui, H., Feinberg, A.P. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
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