Role of long non-coding RNA in cells: Example of the H19/IGF2 locus


In the past decade, studies of non-coding RNAs increase. Non-coding RNAs are divided in two classes: small and long non-coding RNA. It was shown that long non-coding RNAs regulate expression of 70% of genes. Long non-coding RNAs are involved in several cellular processes like epigenetic regulation, dosage compensation, alternative splicing and stem cells maintenance for example. Misregulations of their expression induce diseases such as developmental syndrome or cancer. In this review, we describe some functions of long non-coding RNA in cells. Furthermore, we study the H19/IGF2 cluster: an imprinted genomic locus located on chromosome 11p15.5. Genomic imprinting allows gene expression from a single allele in a parent-origin-dependent manner. This cluster encode for the first long non-coding RNA identified: H19. In 1990, it was established that H19 functions as a riboregulator. Recently, it was shown that H19 is a precursor of microRNA (hsa-miR-675), and several news transcripts were identified at the H19/IGF2 locus. So, the complexity of this locus increasing, in this review, we summarize our current understanding about the H19/IGF2 cluster both in terms of transcription as well as in terms of functions in cells. We highlight the involvement of H19, its new antisense transcript 91H and its microRNA, in the regulation of IGF receptor function and in cell cycle progression.

Share and Cite:

Vennin, C. , Dahmani, F. , Spruyt, N. and Adriaenssens, E. (2013) Role of long non-coding RNA in cells: Example of the H19/IGF2 locus. Advances in Bioscience and Biotechnology, 4, 34-44. doi: 10.4236/abb.2013.45A004.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Esteller, M. (2011) Non-coding RNAs in human disease. Nature Reviews. Genetics, 12, 861-874. doi:10.10398/nrg3074
[2] Knowling, S. and Morris, K.V. (2011) Non-coding RNA and antisense RNA. Nature’s trash or treasure? Biochimie, 93, 1922-1927. doi:10.1016/j.biochi.2011.07.031
[3] Lee, J.T. (2012) Epigenetic regulation by long non-coding RNAs. Science, 338, 1435-1439. doi:10.1126/science.1231776
[4] Rougeulle, C. and Heard, E. (2002) Antisense RNA in imprinting: spreading silence through Air. Trends in Genetics, 18, 434-437. doi:10.1016/S0168-9525(02)0274-X
[5] Sleutels, F., Zwart, R. and Barlow, D.P. (2002) The non-coding Air RNA is required for silencing autosomal imprinted genes. Nature, 415, 810-813. doi:10.1038/415810a
[6] Mitsuya, K., Meguro, M., Lee, M.P., Katoh, M., Schulz, T.C., Kugoh, H., Yoshida, M.A., Niikawa, N., Feinberg, A.P. and Oshimura, M. (1999) LIT1, an imprinted antisense RNA in the human KvLQT1 locus identified by screening for differentially expressed transcripts using monochromosomal hybrids. Human Molecular Genetics, 8, 1209-1217. doi:10.1093/hmg/8.7.1209
[7] Lee, M.P., DeBaun, M.R., Mitsuya, K., Galonek, H.L., Brandenburg, S., Oshimura, M. and Feinberg, A.P. (1999) Loss of imprinting of a paternally expressed transcript, with antisense orientation to KVLQT1, occurs frequently in Beckwith-Wiedemann syndrome and is independent of insulin-like growth factor II imprinting. Proceedings of the National Academy of Sciences of the USA, 96, 52035208. doi:10.1073/pnas.96.9.5203
[8] Du, M., Zhou, W., Beatty, L.G., Weksberg, R. and Sadowski, P.D. (2004) The KCNQ1OT1 promoter, a key regulator of genomic imprinting in human chromosome 11p15.5. Genomics, 84, 288-300. doi:10.1016/j.ygeno.2004.03.008
[9] Pandey, R.R., Ceribelli, M., Singh, P.B., Ericsson, J., Mantovani, R. and Kanduri, C. (2004) NF-Y regulates the antisense promoter, bidirectional silencing, and differential epigenetic marks of the Kcnq1 imprinting control region. Journal of Biological Chemistry, 279, 52685-52693. doi:10.1074/jbc.M408084200
[10] Thakur, N., Tiwari, V.K., Thomassin, H., Pandey, R.R., Kanduri, M., G?nd?r, A., Grange, T., Ohlsson, R. and Kanduri, C. (2004) An antisense RNA regulates the bidirectional silencing property of the Kcnq1 imprinting control region. Molecular and Cellular Biology, 24, 78557862. doi:10.1128/MCB.24.18.7855-7862.2004
[11] Bernard, D., Prasanth, K.V., Tripathi, V., Colasse, S., Nakamura, T., Xuan, Z., Zhang, M.Q., Sedel, F., Jourdren, L., Coulpier, F., et al. (2010) A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression. EMBO Journal, 29, 3082-3093. doi:10.1038/emboj.2010.199
[12] Tripathi, V., Ellis, J.D., Shen, Z., Song, D.Y., Pan, Q., Watt, A.T., Freier, S.M., Bennett, C.F., Sharma, A., Bubulya, P.A., et al. (2010) The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Molecular Cell, 39, 925-938. doi:10.1016/j.molcel.2010.08.011
[13] Loewer, S., Cabili, M.N., Guttman, M., Loh, Y.-H., Thomas, K., Park, I.H., Garber, M., Curran, M., Onder, T., Agarwal, S., et al. (2010) Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nature Genetics, 42, 1113-1117. doi:10.1038/ng.710
[14] Dinger, M.E., Amaral, P.P., Mercer, T.R., Pang, K.C., Bruce, S.J., Gardiner, B.B., Askarian-Amiri, M.E., Ru, K., Soldà, G., Simons, C., et al. (2008) Long non-coding RNAs in mouse embryonic stem cell pluripotency and differentiation. Genome Research, 18, 1433-1445. doi:10.1101/gr.078378.108
[15] Rinn, J.L., Kertesz, M., Wang, J.K., Squazzo, S.L., Xu, X., Brugmann, S.A., Goodnough, L.H., Helms, J.A., Farnham, P.J., Segal, E., et al. (2007) Functional demarcation of active and silent chromatin domains in human HOX loci by non-coding RNAs. Cell, 129, 1311-1323. doi:10.1016/j.cell.2007.05.022
[16] Tano, K. and Akimitsu, N. (2012) Long non-coding RNAs in cancer progression. Frontiers in Genetics, 3, 219. doi:10.3389/fgene.2012.00219
[17] Shore, A.N., Herschkowitz, J.I. and Rosen, J.M. (2012) Non-coding RNAs Involved in Mammary Gland Development and Tumorigenesis: There’s a Long Way to Go. Journal of Mammary Gland Biology and Neoplasia, 17, 43-58. doi:10.1007/s10911-012-9247-3
[18] Gupta, R.A., Shah, N., Wang, K.C., Kim, J., Horlings, H.M., Wong, D.J., Tsai, M.-C., Hung, T., Argani, P., Rinn, J.L., et al. (2010) Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature, 464, 1071-1076. doi:10.1038/nature08975
[19] Cai, X. and Cullen, B.R. (2007) The imprinted H19 noncoding RNA is a primary microRNA precursor. RNA, 13, 313-316. doi:10.1261/rna.351707
[20] Tsang, W.P., Ng, E.K.O., Ng, S.S.M., Jin, H., Yu, J., Sung, J.J.Y. and Kwok, T.T. (2010) Oncofetal H19-derived miR-675 regulates tumor suppressor RB in human colorectal cancer. Carcinogenesis, 31, 350-358. doi:10.1093/carcin/bgp181
[21] Keniry, A., Oxley, D., Monnier, P., Kyba, M., Dandolo, L., Smits, G. and Reik, W. (2012) The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and IGF1r. Nature Cell Biology, 14, 659-665.
[22] Leighton, P.A., Ingram, R.S., Eggenschwiler, J., Efstratiadis, A. and Tilghman, S.M. (1995) Disruption of imprinting caused by deletion of the H19 gene region in mice. Nature, 375, 34-39. doi:10.1038/375034a0
[23] Ripoche, M.A., Kress, C., Poirier, F. and Dandolo, L. (1997) Deletion of the H19 transcription unit reveals the existence of a putative imprinting control element. Genes and Development, 11, 1596-1604. doi:10.1101/gad.11.12.1596
[24] DeChiara, T.M., Robertson, E.J. and Efstratiadis, A. (1991) Parental imprinting of the mouse insulin-like growth factor II gene. Cell, 64, 849-859. doi:10.1016/0092-8674(91)90513-X
[25] Bartolomei, M.S., Webber, A.L., Brunkow, M.E. and Tilghman, S.M. (1993) Epigenetic mechanisms underlying the imprinting of the mouse H19 gene. Genes and Development, 7, 1663-1673. doi:10.1101/gad.7.9.1663
[26] Ferguson-Smith, A.C., Sasaki, H., Cattanach, B.M. and Surani, M.A. (1993) Parental-origin-specific epigenetic modification of the mouse H19 gene. Nature, 362, 751755. doi:10.1038/362751a0
[27] Grandjean, V., O’Neill, L., Sado, T., Turner, B. and Ferguson-Smith, A. (2001) Relationship between DNA methylation, histone H4 acetylation and gene expression in the mouse imprinted IGF2-H19 domain. FEBS Letters, 488, 165-169. doi:10.1016/S0014-5793(00)02349-8
[28] Sasaki, H., Jones, P.A., Chaillet, J.R., Ferguson-Smith, A.C., Barton, S.C., Reik, W. and Surani, M.A. (1992) Parental imprinting: potentially active chromatin of the repressed maternal allele of the mouse insulin-like growth factor II (IGF2) gene. Genes and Development, 6, 18431856. doi:10.1101/gad.6.10.1843
[29] Feil, R., Walter, J., Allen, N.D. and Reik, W. (1994) Developmental control of allelic methylation in the imprinted mouse IGF2 and H19 genes. Development, 120, 2933-2943.
[30] Murrell, A., Heeson, S., Bowden, L., Constancia, M., Dean, W., Kelsey, G. and Reik, W. (2001) An intragenic methylated region in the imprinted IGF2 gene augments transcription. EMBO Reports, 2, 1101-1106. doi:10.1093/embo-reports/kve248
[31] Constancia, M., Dean, W., Lopes, S., Moore, T., Kelsey, G. and Reik, W. (2000) Deletion of a silencer element in IGF2 results in loss of imprinting independent of H19. Nature Genetics, 26, 203-206. doi:10.1038/79930
[32] Tremblay, K.D., Duran, K.L. and Bartolomei, M.S. (1997) A 5’ 2-kilobase-pair region of the imprinted mouse H19 gene exhibits exclusive paternal methylation throughout development. Molecular and Cellular Biology, 17, 43224329.
[33] Drewell, R.A., Arney, K.L., Arima, T., Barton, S.C., Brenton, J.D. and Surani, M.A. (2002a) Novel conserved elements upstream of the H19 gene are transcribed and act as mesodermal enhancers. Development, 129, 12051213.
[34] Takai, D., Gonzales, F.A., Tsai, Y.C., Thayer, M.J. and Jones, P.A. (2001) Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer. Human Molecular Genetics, 10, 2619-2626. doi:10.1093/hmg/10.23.2619
[35] Hark, A.T., Schoenherr, C.J., Katz, D.J., Ingram, R.S., Levorse, J.M. and Tilghman, S.M. (2000) CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/IGF2 locus. Nature, 405, 486-489. doi:10.1038/35013106
[36] Srivastava, M., Hsieh, S., Grinberg, A., Williams-Simons, L., Huang, S.P. and Pfeifer, K. (2000) H19 and IGF2 monoallelic expression is regulated in two distinct ways by a shared cis-acting regulatory region upstream of H19. Genes and Development, 14, 1186-1195.
[37] Murrell, A., Heeson, S. and Reik, W. (2004) Interaction between differentially methylated regions partitions the imprinted genes IGF2 and H19 into parent-specific chromatin loops. Nature Genetics, 36, 889-893.
[38] Kurukuti, S., Tiwari, V.K., Tavoosidana, G., Pugacheva, E., Murrell, A., Zhao, Z., Lobanenkov, V., Reik, W. and Ohlsson, R. (2006) CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to IGF2. Proceedings of the National Academy of Sciences of the USA, 103, 10684-10689. doi:10.1073/pnas.0600326103
[39] Dekker, J., Rippe, K., Dekker, M. and Kleckner, N. (2002) Capturing chromosome conformation. Science, 295, 13061311. doi:10.1126/science.1067799
[40] Taylor, E.R., Seleiro, E.A. and Brickell, P.M. (1991) Identification of antisense transcripts of the chicken insulin-like growth factor-II gene. Journal of Molecular Endocrinology, 7, 145-154. doi:10.1677/jme.0.0070145
[41] Moore, T., Constancia, M., Zubair, M., Bailleul, B., Feil, R., Sasaki, H. and Reik, W. (1997) Multiple imprinted sense and antisense transcripts, differential methylation and tandem repeats in a putative imprinting control region upstream of mouse IGF2. Proceedings of the National Academy of Sciences USA, 94, 12509-12514. doi:10.1073/pnas.94.23.12509
[42] Okutsu, T., Kuroiwa, Y., Kagitani, F., Kai, M., Aisaka, K., Tsutsumi, O., Kaneko, Y., Yokomori, K., Surani, M.A., Kohda, T., et al. (2000) Expression and imprinting status of human PEG8/IGF2as, a paternally expressed antisense transcript from the IGF2 locus, in Wilms’ tumors. Journal of Biochemistry, 127, 475-483. doi:10.1093/oxfordjournals.jbchem.a022630
[43] Duart-Garcia, C. and Braunschweig, M.H. (2013) The IGF2as transcript is exported into cytoplasm and associated with polysomes. Biochemical Genetics, 51, 119-130. doi:10.1007/s10528-012-9547-8
[44] Berteaux, N., Aptel, N., Cathala, G., Genton, C., Coll, J., Daccache, A., Spruyt, N., Hondermarck, H., Dugimont, T., Curgy, J.-J., et al. (2008) A novel H19 antisense RNA overexpressed in breast cancer contributes to paternal IGF2 expression. Molecular and Cellular Biology, 28, 6731-6745. doi:10.1128/MCB.02103-07
[45] Tran, V.G., Court, F., Duputié, A., Antoine, E., Aptel, N., Milligan, L., Carbonell, F., Lelay-Taha, M.-N., Piette, J., Weber, M., et al. (2012) H19 antisense RNA can up-regulate IGF2 transcription by activation of a novel promoter in mouse myoblasts. PLoS ONE, 7, e37923. doi:10.1371/journal.pone.0037923
[46] Onyango, P. and Feinberg, A.P. (2011) A nucleolar protein, H19 opposite tumor suppressor (HOTS), is a tumor growth inhibitor encoded by a human imprinted H19 antisense transcript. Proceedings of the National Academy of Sciences of the USA, 108, 16759-16764. doi:10.1073/pnas.1110904108
[47] Court, F., Baniol, M., Hagege, H., Petit, J.S., Lelay-Taha, M.-N., Carbonell, F., Weber, M., Cathala, G. and Forne, T. (2011) Long-range chromatin interactions at the mouse IGF2/H19 locus reveal a novel paternally expressed long non-coding RNA. Nucleic Acids Research, 39, 5893-5906. doi:10.1093/nar/gkr209
[48] Pachnis, V., Belayew, A. and Tilghman, S.M. (1984) Locus unlinked to alpha-fetoprotein under the control of the murine raf and Rif genes. Proceedings of the National Academy of Sciences of the USA, 81, 5523-5527. doi:10.1073/pnas.81.17.5523
[49] Pachnis, V., Brannan, C.I. and Tilghman, S.M. (1988) The structure and expression of a novel gene activated in early mouse embryogenesis. The EMBO Journal, 7, 673681.
[50] Zhang, Y. and Tycko, B. (1992) Monoallelic expression of the human H19 gene. Nature Genetics, 1, 40-44. doi:10.1038/ng0492-40
[51] Joubel, A., Curgy, J.J., Pelczar, H., Begue, A., Lagrou, C., Stehelin, D. and Coll, J. (1996) The 5’ part of the human H19 RNA contains cis-acting elements hampering its translatability. Cellular and Molecular Biology, 42, 11591172.
[52] Brannan, C.I., Dees, E.C., Ingram, R.S. and Tilghman, S.M. (1990) The product of the H19 gene may function as an RNA. Molecular and Cellular Biology, 10, 28-36.
[53] Yang, J.-S. and Lai, E.C. (2011) Alternative miRNA biogenesis pathways and the interpretation of core miRNA pathway mutants. Molecular Cell, 43, 892-903. doi:10.1016/j.molcel.2011.07.024
[54] Li, Y.M., Franklin, G., Cui, H.M., Svensson, K., He, X.B., Adam, G., Ohlsson, R. and Pfeifer, S. (1998) The H19 transcript is associated with polysomes and may regulate IGF2 expression intrans. Journal of Biological Chemistry, 273, 28247-28252. doi:10.1074/jbc.273.43.28247
[55] Wilkin, F., Paquette, J., Ledru, E., Hamelin, C., Pollak, M., Deal, C.L. and Mamelin, C. (2000) H19 sense and antisense transgenes modify insulin-like growth factor-II mRNA levels. European Journal of Biochemistry, 267, 4020-4027. doi:10.1046/j.1432-1327.2000.01438.x
[56] Lottin, S., Adriaenssens, E., Dupressoir, T., Berteaux, N., Montpellier, C., Coll, J., Dugimont, T. and Curgy, J.J. (2002) Overexpression of an ectopic H19 gene enhances the tumorigenic properties of breast cancer cells. Carcinogenesis, 23, 1885-1895. doi:10.1093/carcin/23.11.1885
[57] Poirier, F., Chan, C.T., Timmons, P.M., Robertson, E.J., Evans, M.J. and Rigby, P.W. (1991) The murine H19 gene is activated during embryonic stem cell differentiation in vitro and at the time of implantation in the developing embryo. Development, 113, 1105-1114.
[58] Lustig, O., Ariel, I., Ilan, J., Lev-Lehman, E., De-Groot, N. and Hochberg, A. (1994) Expression of the imprinted gene H19 in the human fetus. Molecular Reproduction and Development, 38, 239-246. doi:10.1002/mrd.1080380302
[59] Ohlsson, R., Hedborg, F., Holmgren, L., Walsh, C. and Ekström, T.J. (1994) Overlapping patterns of IGF2 and H19 expression during human development: Biallelic IGF2 expression correlates with a lack of H19 expression. Development, 120, 361-368.
[60] Hemberger, M., Redies, C., Krause, R., Oswald, J., Walter, J. and Fundele, R.H. (1998) H19 and IGF2 are expressed and differentially imprinted in neuroecto-dermderived cells in the mouse brain. Development Genes and Evolution, 208, 393-402.doi:10.1007/s004270050195
[61] Douc-Rasy, S., Coll, J., Barrois, M., Joubel, A., Prost, S., Dozier, C., Stéhelin, D. and Riou, G. (1993) Expression of the human fetal BAC/H19 gene in invasive cancer. International Journal of Oncology, 2, 753-758.
[62] Okamoto, K., Morison, I.M., Taniguchi, T. and Reeve, A.E. (1997) Epigenetic changes at the insulin-like growth factor II/H19 locus in developing kidney is an early event in Wilms tumorigenesis. Proceedings of the National Academy of Sciences of the USA, 94, 5367-5371. doi:10.1073/pnas.94.10.5367
[63] Steenman, M.J., Rainier, S., Dobry, C.J., Grundy, P., Horon, I.L. and Feinberg, A.P. (1994) Loss of imprinting of IGF2 is linked to reduced expression and abnormal methylation of H19 in Wilms’ tumour. Nature Genetics, 7, 433-439. doi:10.1038/ng0794-433
[64] Dugimont, T., Curgy, J.J., Wernert, N., Delobelle, A., Raes, M.B., Joubel, A., Stehelin, D. and Coll, J. (1995) The H19 gene is expressed within both epithelial and stromal components of human invasive adenocarcinomas. Biology of the Cell, 85, 117-124. doi:10.1016/0248-4900(96)85272-5
[65] Adriaenssens, E., Lottin, S., Dugimont, T., Fauquette, W., Coll, J., Dupouy, J.P., Boilly, B. and Curgy, J.J. (1999) Steroid hormones modulate H19 gene expression in both mammary gland and uterus. Oncogene, 18, 4460-4473. doi:10.1038/sj.onc.1202819
[66] Ariel, I., Ayesh, S., Perlman, E.J., Pizov, G., Tanos, V., Schneider, T., Erdmann, V.A., Podeh, D., Komitowski, D., Quasem, A.S., et al. (1997) The product of the imprinted H19 gene is an oncofetal RNA. Molecular Pathology, 50, 34-44. doi:10.1136/mp.50.1.34
[67] 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. doi:10.1016/0090-4295(95)80030-1
[68] Elkin, M., Shevelev, A., Schulze, E., Tykocinsky, M., Cooper, M., Ariel, I., Pode, D., Kopf, E., De Groot, N. and Hochberg, A. (1995). The expression of the imprinted H19 and IGF2 genes in human bladder carcinoma. FEBS Letters, 374, 57-61. doi:10.1016/0014-5793(95)01074-O
[69] Yang, F., Bi, J., Xue, X., Zheng, L., Zhi, K., Hua, J. and Fang, G. (2012) Up-regulated long non-coding RNA H19 contributes to proliferation of gastric cancer cells. FEBS Journal, 279, 3159-3165. doi:10.1111/j.1742-4658.2012.08694.x
[70] Dugimont, T., Montpellier, C., Adriaenssens, E., Lottin, S., Dumont, L., Iotsova, V., Lagrou, C., Stéhelin, D., Coll, J. and Curgy, J.J. (1998) The H19 TATA-less promoter is efficiently repressed by wild-type tumor suppressor gene product p53. Oncogene, 16, 2395-2401. doi:10.1038/sj.onc.1201742
[71] Adriaenssens, E., Dumont, L., Lottin, S., Bolle, D., Leprêtre, A., Delobelle, A., Bouali, F., Dugimont, T., Coll, J. and Curgy, J.J. (1998) H19 overexpression in breast adenocarcinoma stromal cells is associated with tumor values and steroid receptor status but independent of p53 and Ki-67 expression. American Journal of Pathology, 153, 1597-1607. doi:10.1016/S0002-9440(10)65748-3
[72] Matouk, I.J., DeGroot, N., Mezan, S., Ayesh, S., Abu-lail, R., Hochberg, A. and Galun, E. (2007) The H19 noncoding RNA is essential for human tumor growth. PLoS ONE, 2, e845. doi:10.1371/journal.pone.0000845
[73] Matouk, I.J., Mezan, S., Mizrahi, A., Ohana, P., Abu-Lail, R., Fellig, Y., Degroot, N., Galun, E. and Hochberg, A. (2010) The oncofetal H19 RNA connection: Hypoxia, p53 and cancer. Biochimica et Biophysica Acta, 1803, 443-451.
[74] Ravi, R., Mookerjee, B., Bhujwalla, Z.M., Sutter, C.H., Artemov, D., Zeng, Q., Dillehay, L.E., Madan, A., Semenza, G.L. and Bedi, A. (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes and Development, 14, 34-44.
[75] Berteaux, N., Lottin, S., Monté, D., Pinte, S., Quatannens, B., Coll, J., Hondermarck, H., Curgy, J.-J., Dugimont, T. and Adriaenssens, E. (2005) H19 mRNA-like non-coding RNA promotes breast cancer cell proliferation through positive control by E2F1. Journal of Biological Chemistry, 280, 29625-29636. doi:10.1074/jbc.M504033200

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.